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					                            Clinical Study Report
Clinical Phase: I
Version and date: Final Version – 27 July 2007
Report number:
Protocol number:
Trial number: TMC120-C131 / IPM008
Drug (number): TMC120
Title: Double-blind, randomized, placebo controlled trial to study safety, local and systemic
availability of TMC120 from a vaginal ring
Indication: PREVENTION OF HIV-1 INFECTION
Trial design: This Phase I trial assessed the feasibility of using a vaginal ring to deliver the
candidate microbicide TMC120 for 7 days. The study population consisted of 13 healthy sexually
abstinent women. Safety and tolerability were assessed through clinical and laboratory
assessments. Feasibility of drug delivery was assessed by measuring TMC120 concentrations in
vaginal fluids, vaginal and cervical epithelial tissue, and plasma.
Trial initiation date: 27 June 2005
Trial completion date: 04 August 2005
Principal investigator(s): Luc Van Bortel, M.D., Drug Research Unit, UZ Ghent
Subinvestigator: Marleen Temmerman, M.D., Department of Gynaecology, UZ Ghent
Trial location: Drug Research Unit Gent, De Pintelaan 185, 9000 Ghent, Belgium
                  Tel.: +32 (0)9 240 55 44 / Fax: +32 (0)9 240 56 50
Sponsor: Annalene Nel MBChB, Ph.D., Chief Medical Officer
              International Partnership for Microbicides (IPM)
              1010 Wayne Avenue, Suite 1450
              Silver Spring, Maryland, USA, 20910
              Tel.: (301) 608-2221 / Fax: (301) 608-2241
Co-Sponsor: Tibotec Pharmaceuticals Ltd., Little Island, Co Cork; Ireland
Authors: A.M. Nel, J. Romano, K. Douville, M. Mitchnick, Z. Rosenberg
GCP compliance: This trial was performed in compliance with Good Clinical Practices, including
the archiving of essential documents and the principles of the Declaration of Helsinki.
Clinical Study Report TMC120-C131/IPM008                                                    2/132




SYNOPSIS
 Sponsor: International Partnership for Microbicides, Tibotec Pharmaceutical Ltd.
 Active ingredient: TMC120
 Title: Double-blind, randomized, placebo controlled trial to study safety, local and systemic
 availability of TMC120 from a vaginal ring
 Investigator: Luc Van Bortel, M.D.
 Subinvestigator: Marleen Temmerman, M.D.
 Study centre: Drug Research Unit, UZ Ghent, De Pintelaan 185, 9000 Ghent, Belgium
 References: see section 7
 Trial period:                                          Phase of development: I
 Start: 27 June 2005
 End: 04 August 2005
 Indication: Prevention of HIV-1 infection
 Objectives: The purpose of this study was to evaluate the feasibility of using a vaginal ring to
 deliver the candidate microbicide TMC120. Specific objectives were to:
     - Assess the safety and tolerability of 7-day use of a vaginal ring containing TMC120.
     - Assess TMC120 concentrations in vaginal fluids, vaginal and cervical epithelial tissue,
        and plasma during and after 7-day use of a vaginal ring containing TMC120.
     - Challenge cervical tissue biopsies ex-vivo in the laboratory with HIV-1 according to the
        microbicide screening model in cellular and human cervical tissue.
 Methodology: This study evaluated the feasibility of using a vaginal ring to deliver TMC120
 as a vaginal microbicide. A randomized, double-blind placebo controlled phase I design was
 employed to assess 7-day use of a vaginal ring containing 25 mg TMC120. Thirteen healthy
 sexually abstinent women underwent 7-day exposure to a 25 mg TMC120 ring or a placebo
 ring containing no investigational agent. Feasibility was assessed in terms of safety and
 tolerability as well as drug delivery.
 No. of investigators: 1
 No. of participants: Planned: 13
                         Analyzed: 13
 Participant selection:
 • Inclusion criteria:
     - Female, age 18-50 years, inclusive.
     - Willing and able to provide written informed consent.
     - HIV-uninfected and otherwise healthy, based on medical history, vital signs, physical
        examination, urinalysis, laboratory evaluations for genital infections, and laboratory
        evaluations of hematology, liver and renal function.
     - Willing to abstain from sexual activity and from use of vaginal products while
        participating in the study.
     - Currently using oral contraceptives for pregnancy prevention.
     - Willing to use oral contraceptives as needed to avoid menstruation while taking part in
        this study.
 • Exclusion criteria:
     - History of alcoholism, drug abuse, psychosis, antagonistic personality, poor motivation,
        or other emotional or intellectual problems that are likely to invalidate the informed
        consent process or adversely impact compliance with protocol requirements.
     - History of allergy to TMC120 or to the constituents of the vaginal ring.
     - History of hypersensitivity to propofol, or other contraindication to general anesthesia
        or sedation.
     - History of diagnosis of and/or treatment for a sexually transmitted disease within the
        last three months.
     - History of genital tract surgery within the last month.
     - Currently pregnant or breastfeeding, or within two months of last pregnancy outcome.
     - Currently or within one month of participating in any other clinical research study
        involving investigational or marketed products.
     - Current diagnosis of any genital infection.



IPM                                        27 July 2007                               Final Version
Clinical Study Report TMC120-C131/IPM008                                                           3/132




SYNOPSIS, Cont’d
 • Exclusion criteria, cont’d:
    - Current vulvar or vaginal symptoms/abnormalities that could influence the study
      results.
    - Current non-iatrogenic pelvic/colposcopic exam findings involving deep epithelial
      disruption.
    - Smoking more than 10 cigarettes/day.
 Treatment
 Medication                                 TMC120                        Placebo
 Form – dosing route              Silicone elastomer vaginal     Silicone elastomer vaginal
                                ring containing one core with  ring without active compound
                                       active compound

                                             Vaginal ring                       Vaginal ring
 Batch number                                05DR03402                          05DR03501
 Dosage                                        25 mg                              None
 Duration of treatment                                       7 days
 Duration of trial              At least 15 days: 1 screening visit, followed by 7 days of
                                exposure to placebo or TMC120, respectively, and one
                                follow-up visit one week after the last treatment day.
                                Screening could be no longer than 8 weeks prior to first day of
                                treatment.
 Disallowed medication          Participants were instructed not to use any vaginal
                                medications, preparations, or other products while in the trial.
 Assessments                    Part A: Schedule of Study Visits and Procedures
                                                 Enrollment
                                 Screening

                                 -8 weeks




                                                                      Day 2-6




                                                                                                 Day 14
                                                 Day 0



                                                              Day 1




                                                                                     Day 7
                                 up to




                                                                                                 Exit
                                   V1          V2        V3         V4          V5                V6
 Screening visita                   X
 Eligibility                        X           X
 Physical examination               X           X
 Vital signs                        X           X         X                     X
 Pregnancy testb                    X           X                               X
 Urinalysis                         X           X                               X
 Pelvic/ Colposcopic                X           X         X                     X                  X
 examination
 Hematology, liver and renal        X           X                               X
 function
 Placebo ring/TMC120 ring                       X
 insertion
 Placebo ring/ TMC120 ring                                                      X
 removal
 Symptom diary                      Xc          X         X          X          X
 Concomitant medication                         X         X          X          X                  X
 Adverse events                                 X         X          X          X                  X
 a
   Screening visit included signing of informed consent, recording of demographic data,
   medical history, ECG and testing for HIV and genital infections (bacterial vaginosis,
   candida, chlamydia, gonorrhea, syphilis, trichomonas, herpes).
 b
   Serum pregnancy test at screening and urine pregnancy test on Day 0 and Day 7.
 c
   Symptom diary completion to start (on study Day –7).




IPM                                          27 July 2007                                    Final Version
Clinical Study Report TMC120-C131/IPM008                                                                                4/132




SYNOPSIS, Cont’d
 Assessments, cont’d              Part B: Schedule of Specimen Collection for TMC120
                                  Concentrations




                                                                                                     Day 7 PrRR



                                                                                                                        Day 7 PRR
                                                           Day 2 PRI



                                                                         Day 3 PRI



                                                                                         Day 5 PRI
                                             24h PRI
                                   4h PRI
                                   Day 0



                                             Day 1
                                    V2         V3       V4         V4       V4        V5  V5
 Group 1     TMC120 (n= 4)          B, S     B, S, L                        S, L     B, S T
             Placebo (n=1)          B, S     B, S, L                        S, L     B, S T
 Group 2 TMC120 (n=3)               B, S      B, S      S, L                         B, S T
             Placebo (n=1)          B, S      B, S      S, L                         B, S T
 Group 3 TMC120 (n=3)               B, S      B, S                 S, L              B, S T
             Placebo (n=1)          B, S      B, S                 S, L              B, S T
 PRI = post ring insertion; PrRR = pre ring removal; PRR = post ring removal; B = blood
 collection; S = collection of vaginal fluids with sno-strips; L = cervicovaginal lavage;
 T = cervical and vaginal tissue biopsy (~3 mm in diameter and thickness each).
 Statistical methods              Descriptive statistics, frequency tabulation

Main Features of the Participant Sample and Summary of the Results
 Baseline characteristics -                                            All participants
 participant disposition                                                    (n=13)
 Number of participants entered                                           13 (0/13)
 (M/F)                                                                 25.0 (19 – 46)
 Age: median (min-max), years
 Drop-outs                                                                           0

 Safety
 n = number of participants with data           Placebo                25 mg TMC120                  Whole trial
 (percentage, %)                                 (n=3)                     (n=10)                     (n=13)
 Adverse events (AE)
 Most frequently reported AEs:
 • Vaginal hemorrhage                             2 (67)              4 (40)            6 (46)
 • Fatigue                                           0                2 (20)            2 (15)
 • Urinary incontinence                              0                2 (20)            2 (15)
 No. (%) with one or more AE                      2 (67)              8 (80)           10 (77)
 No. (%) of deaths                                   0                   0                 0
 No. (%) with one or more other SAE                  0                   0                 0
 No. (%) treatment stopped due to AE                 0                   0                 0
 Clinical laboratory parameters             No clinically relevant changes over time for any of the
                                            laboratory parameters.
                                            One treatment-emergent graded laboratory
                                            abnormality was reported, i.e., grade 1 hypokalemia,
                                            for a participant receiving placebo treatment. Most
                                            treatment-emergent nongraded laboratory
                                            abnormalities were related to hematology.
                                            No relevant differences in the incidence of nongraded
                                            laboratory abnormalities between TMC120 and
                                            placebo treatments were observed.
 Urinalysis                                 No clinically relevant changes over time in urinalysis
                                            results.
                                            No urinalysis abnormalities were reported as AE.



IPM                                         27 July 2007                                                          Final Version
Clinical Study Report TMC120-C131/IPM008                                                       5/132




SYNOPSIS, Cont’d
 Safety, cont’d
 Pelvic examination                        A clinically significant abnormality (uterine cervix
                                           ulcer) was observed after pelvic examination of one
                                           participant receiving TMC120. This was reported as a
                                           grade 2 AE, doubtfully drug-related.
                                           No clinically relevant changes from Day 1 in vaginal
                                           ecology pH or Nugent scores were observed on
                                           Day 14 in placebo or TMC120 treatment groups.
 Vital signs                               No clinically relevant changes over time in vital signs
                                           parameters were reported.
                                           No vital sign abnormalities were reported as AE.

 TMC120 concentrations in                   Cervix          Vaginal ring area     Vaginal introitus
 vaginal fluid and tissue (ng/g)                                                       area
 Median
 (range)
 Placebo treatment
 • Vaginal fluids
    − Day 1, 4h PRI                           0.0                  0.0                   0.0
                                            (0 – 0)              (0 – 0)               (0 – 0)
      − Day 1, 24h PRI                        3.9                  0.0                   7.9
                                            (0 – 8)              (0 – 6)              (0 – 39)
      − Day 7                                 0.0                  0.0                   0.0
                                            (0 – 0)              (0 – 6)               (0 – 0)
 • Tissue, Day 7                               -                  10.20                 4.59
                                                              (3.2 – 11.6)a         (2.0 – 12.4)a
 25 mg TMC120 treatment
 • Vaginal fluids
    − Day 1, 4h PRI                        2765.0                5600.0               1695.0
                                       (377 – 11700)         (1980 – 21200)        (246 – 9950)
      − Day 1, 24h PRI                     3070.0                6480.0               3190.0
                                        (618 – 8210)          (2470 – 9140)        (265 – 7060)
      − Day 7                              1520.0                5805.0               3810.0
                                        (205 – 6170)         (1290 – 18500)        (186 – 7990)
 • Tissue, Day 7                           691.50                2475.50             1805.00
                                      (272.0 – 4510.0)      (397.0 – 9901.0)     (151.0 – 5060.0)
 PRI = post ring insertion
 a
   TMC120 concentrations in all biopsy samples collected from the placebo group were above
 the LLOQ of the assay (0.005 ng/sample) but below 12.4 ng/g. Such concentrations could
 possibly be attributed to contamination either at the manufacturing site, at the clinic, or at the
 bioanalytical lab.

 TMC120 concentrations in plasma (ng/mL)
 Median (range)
 Placebo treatment
    − Day 1, 4h PRI                                              < 0.005
    − Day 1, 24h PRI                                             < 0.005
    − Day 7                                                      < 0.005
 25 mg TMC120 treatment
    − Day 1, 4h PRI                                          0.02 (0.0 – 0.1)
    − Day 1, 24h PRI                                         0.03 (0.0 – 0.1)
    − Day 7                                                  0.04 (0.0 – 0.1)



IPM                                        27 July 2007                                 Final Version
Clinical Study Report TMC120-C131/IPM008                                                6/132




SYNOPSIS, Cont’d
 Conclusions

 Seven-day use of a vaginal ring containing TMC120 was generally safe and well tolerated
 among healthy women.
 TMC120 was detectable in blood at very low concentrations. These results suggest that
 vaginal rings can safely and feasibly deliver TMC120. However, no definite conclusions can
 be drawn due to the low sample size.


 Date of the report: 27 July 2007




IPM                                        27 July 2007                           Final Version

				
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