A Study to Characterize Diclofenac's Plasma and Knee Exposure After Application of Diclofenac Gel to the Knee of Subjects With Osteoarthritis That Have a Scheduled Arthroplasty
Condition: Pain
MeSH terms: Osteoarthritis
Intervention: Diclofenac Diethylamine (DDEA) gel; Placebo gel
Intervention description: Diclofenac Diethylamine (DDEA) gel consists of 2.32% DDEA. DDEA gel will be applied twice a day for 7 days topically first and last dose by trained nurse (or designee) at study site and doses in between by a trained nurse at participant's home or other convenient location. Participants will be admitted on the day before the scheduled surgery (Day 7). The last dose of study treatment will be administered at the study site 12 hours (window -1/+3 hrs) prior to arthroplasty surgery.If surgery is delayed by up to 7 days dosing with DDEA gel twice daily can continue up to 14 days. If the surgery is delayed by more than 7 days, the participant should be withdrawn from the study.; Placebo gel will be applied twice a day for 7 days topically first and last dose by trained nurse (or designee) at study site and doses in between by a trained nurse at participant's home or other convenient location. Participants will be admitted on the day before the scheduled surgery (Day 7). The last dose of placebo gel will be administered at the study site 12 hours (window -1/+3 hrs) prior to arthroplasty surgery. If surgery is delayed by up to 7 days dosing with placebo gel twice daily can continue up to 14 days. If the surgery is delayed by more than 7 days, the participant should be withdrawn from the study.
Intervention MeSH terms: Diclofenac
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 47.0
Sex: All
Minimum age: 50 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to evaluate the exposure of diclofenac in the plasma and in the
      knee joint following topical administration of DDEA gel 4 gram (g) applied twice daily for 7
      days.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Evidence of a personally signed and dated informed consent document indicating that
             the participant has been informed of all pertinent aspects of the study before any
             assessment is performed.

          -  Male and female participants who, at the time of screening, are ≥ 50 years of age.

          -  Participant has a diagnosis of OA of the knee requiring arthroplasty and is scheduled
             for single knee arthroplasty, with radiographic evidence within last 6 months
             confirming Kellgren Lawrence grade of 2 or more.

          -  Participant is in general good physical health and deemed fit for surgery, as judged
             by the investigator and no clinically relevant abnormalities identified by a detailed
             medical history, full physical examination, including blood pressure and pulse rate
             measurement, respiratory rate and temperature measurement, 12 lead ECG or clinical
             laboratory tests.

          -  Body Mass Index (BMI) of 17.5 to less than 40 kg/m2; and a total body weight >50 kg
             (110 lbs).

          -  Participants who are willing and able to comply with scheduled visits, treatment plan,
             laboratory tests, and other study procedures.

          -  Female participants of childbearing potential and at risk for pregnancy must agree to
             use a highly effective method of contraception throughout the study and for at least
             21 days after the last dose of assigned treatment. Female participants who are not of
             childbearing potential must meet following requirements: Female participants who are
             of childbearing potential and are sexually active and at risk for pregnancy must agree
             to use a highly effective method of contraception consistently and correctly for the
             duration of the active study period (onwards from screening) and for at least 21 days
             after the last dose of investigational product. The investigator or his or her
             designee, in consultation with the participant, will confirm that the participant has
             selected an appropriate method of contraception for the individual participant from
             the permitted list of contraception methods (see below) and instruct the participant
             in its consistent and correct use. Participants need to affirm that they meet the
             criteria for the correct use of at least 1 of the selected methods of contraception.
             The investigator or his or her designee will discuss with the participant the need to
             use highly effective contraception consistently and correctly according to the
             schedule of activities and document such conversation in the participant's chart. In
             addition, the investigator or his or her designee will instruct the participant to
             call immediately if the selected contraception method is discontinued or if pregnancy
             is known or suspected in the participant. Highly effective methods of contraception
             are those that, alone or in combination, result in a failure rate of less than 1% per
             year when used consistently and correctly (i.e., perfect use) and include the
             following a)Established use of oral, inserted, injected, transdermal, or implanted
             hormonal methods of contraception is allowed provided the participant plans to remain
             on the same treatment throughout the entire study and has been using that hormonal
             contraceptive for an adequate period of time to ensure effectiveness as deemed
             appropriate by the investigator, b) Correctly placed copper-containing intrauterine
             device (IUD), c) Male condom or female condom used with a spermicide (i.e., foam, gel,
             film, cream, or suppository), d) Male sterilization with absence of sperm in the
             post-vasectomy ejaculate e) Bilateral tubal ligation / bilateral salpingectomy or
             bilateral tubal occlusive procedure (provided that occlusion has been confirmed in
             accordance with the device's label), f)Female who meets the criteria for
             non-childbearing potential as described below. Female participants of non-childbearing
             potential must meet at least one of the following criteria: 1) Achieved postmenopausal
             status, defined as follows: cessation of regular menses for at least 12 consecutive
             months with no alternative pathological or physiological cause; status may be
             confirmed by a serum follicle-stimulating hormone (FSH) level confirming the
             post-menopausal state, 2) Have undergone a documented hysterectomy and/or bilateral
             oophorectomy, 3) Have medically confirmed ovarian failure.

        All other female participants (including females with tubal ligations) will be considered
        to be of childbearing potential.

        Exclusion Criteria:

          -  Participants who are investigational site staff members directly involved in the
             conduct of the study and their family members, site staff members otherwise supervised
             by the investigator, or participants who are GSK employees directly involved in the
             conduct of the study.

          -  Participation in other studies involving investigational drug(s) within one month
             prior to study entry and/or during study participation.

          -  Acute or chronic medical or psychiatric condition or laboratory abnormality that may
             increase the risk associated with study participation or investigational product
             administration or may interfere with the interpretation of study results and, in the
             judgment of the investigator, would make the participant inappropriate for entry into
             this study.

          -  Pregnant female participants.

          -  Breastfeeding female participants.

          -  Known or suspected intolerance or hypersensitivity to the study materials (or closely
             related compounds) or any of their stated ingredients.

          -  Participants in whom attacks of asthma, angioedema, urticaria, or acute rhinitis are
             precipitated by acetylsalicylic acid or other non-steroidal anti-inflammatory drugs
             (NSAIDs).

          -  Participants whose skin around the knee is broken, diseased or has skin wounds or open
             injuries.

          -  Unwilling or unable to comply with the following lifestyle guidelines described in the
             protocol or investigator instructions: a) Meals and Dietary Restrictions: No specific
             meal or dietary restriction is required for the study. Participants will follow the
             perioperative guidance with respect to meals and dietary restrictions as provided by
             the surgical center. Participants must abstain from all food and drink (except water)
             at least 4 hours prior to any safety laboratory evaluations, b)Alcohol, Caffeine and
             Tobacco: participants will follow the perioperative guidance with respect to alcohol
             and caffeine intake and use of tobacco- or nicotine containing products as provided by
             the surgical center, c) Activity: participants will follow the perioperative guidance
             with respect to activity as provided by the surgical center, d) Contraception: Female
             participants who are of childbearing potential and are sexually active and at risk for
             pregnancy must agree to use a highly effective method of contraception consistently
             and correctly for the duration of the active study period (onwards from screening) and
             for at least 21 days after the last dose of investigational product. The investigator
             or his or her designee, in consultation with the participant, will confirm that the
             participant has selected an appropriate method of contraception for the individual
             participant from the permitted list of contraception methods (see below) and instruct
             the participant in its consistent and correct use. Participants need to affirm that
             they meet the criteria for the correct use of at least 1 of the selected methods of
             contraception. The investigator or his or her designee will discuss with the
             participant the need to use highly effective contraception consistently and correctly
             according to the schedule of activities and document such conversation in the
             participant's chart. In addition, the investigator or his or her designee will
             instruct the participant to call immediately if the selected contraception method is
             discontinued or if pregnancy is known or suspected in the participant.

        Highly effective methods of contraception are those that, alone or in combination, result
        in a failure rate of less than 1% per year when used consistently and correctly (i.e.,
        perfect use) and include the following: 1) Established use of oral, inserted, injected,
        transdermal, or implanted hormonal methods of contraception is allowed provided the
        participant plans to remain on the same treatment throughout the entire study and has been
        using that hormonal contraceptive for an adequate period of time to ensure effectiveness as
        deemed appropriate by the investigator, 2) Correctly placed copper-containing intrauterine
        device (IUD), 3) Male condom or female condom used with a spermicide (i.e., foam, gel,
        film, cream, or suppository), 4) Male sterilization with absence of sperm in the
        post-vasectomy ejaculate, 5) Bilateral tubal ligation / bilateral salpingectomy or
        bilateral tubal occlusive procedure (provided that occlusion has been confirmed in
        accordance with the device's label), 6)Female who meets the criteria for non-childbearing
        potential as described below. Female participants of non-childbearing potential must meet
        at least one of the following criteria: a) Achieved postmenopausal status, defined as
        follows: cessation of regular menses for at least 12 consecutive months with no alternative
        pathological or physiological cause; status may be confirmed by a serum
        follicle-stimulating hormone (FSH) level confirming the post-menopausal state, b) Have
        undergone a documented hysterectomy and/or bilateral oophorectomy, c) Have medically
        confirmed ovarian failure.

        All other female participants (including females with tubal ligations) will be considered
        to be of childbearing potential e) Screen Failures: Screen failures are defined as
        participants who consent to participate in the clinical study but are not subsequently
        randomized. In order to ensure transparent reporting of screen failure participants, a
        minimal set of screen failure information will include screening number, date of screening,
        demography (gender, year of birth, age), screen failure details (e.g., withdrawal of
        consent), eligibility criteria, and any serious adverse events. Screening failures will be
        replaced in the recruitment schedule until the required number of participants are
        randomized. Individuals who do not meet the criteria for participation in this study
        (screen failure) may not be re-screened, f) Sponsor's Qualified Medical Personnel: The
        contact information for the sponsor's appropriately qualified medical personnel for the
        study is documented in the study contact list located in the supporting study
        documentation. The contact number can be used by investigational staff if they are seeking
        advice on medical questions or problems; however, it should be used only in the event that
        the established communication pathways between the investigational site and the study team
        are not available. It is therefore intended to augment, but not replace, the established
        communication pathways between the investigational site and the study team for advice on
        medical questions or problems that may arise during the study. The contact number is not
        intended for use by the participant directly, and if a participant calls that number, he or
        she will be directed back to the investigational site. To facilitate access to
        appropriately qualified medical personnel on study-related medical questions or problems,
        participants are provided with a contact card. The contact card contains, at a minimum,
        protocol identifiers, participant study numbers, contact information for the
        investigational site, and contact details in the event that the investigational site staff
        cannot be reached to provide advice on a medical question or problem identified from the
        participant's healthcare professional other than the investigator.

          -  Use of prescription or nonprescription drugs (unless deemed necessary by
             investigator), NSAIDs, COX-2 inhibitors and dietary supplements within 7 days or 5
             half-lives (whichever is longer) prior to the first dose of study treatment and during
             the study. Specifically if, during the washout period or the treatment period, the
             participant is unwilling to avoid the use of any topical or systemic analgesic or
             anti-inflammatory treatments other than the study medication, the rescue medication,
             and if needed codeine or tramadol.

          -  Use of one or more of the following treatments prior to the screening visit or between
             screening and baseline visit: a) any topical NSAID treatment between screening and
             baseline visit, b) any intra-articular or peri-articular procedures or injections in
             either knee within the previous 3 months, c) any systemic treatment with
             corticosteroids within the previous 6 weeks (topical treatments with corticosteroids
             not related to either knee are permitted up to screening visit), d) any
             chondroprotectant or disease-modifying OA drugs, such as glucosamine or chondroitin
             sulfate, unless dose was stable over the previous month and will be maintained
             throughout the study, e) any systemic anti-inflammatory or analgesic drugs at
             screening if 5 times their elimination halftime exceeds 7 days (i.e., if half-life >
             33.6 hrs), f) anticoagulants such as warfarin or heparin in the preceding week or
             antiaggregants within the previous month other than aspirin at stable low doses
             started at least one month before randomization and kept at a constant dose throughout
             the study or anticoagulant therapy for surgery, g) any other investigational drugs
             within the previous month or 5 half lives preceding the first dose of investigational
             product (whichever is longer).

          -  A positive urine drug screen during Screening (Day -7).

          -  Any condition possibly affecting drug absorption (e.g., gastrectomy).

          -  History of regular alcohol consumption exceeding 14 drinks/week (1 drink = 5 ounces
             (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor)
             within 6 months of Screening.

          -  Participants who have previously been enrolled in this study.