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Transcript
K2 BIOMEDICAL
A Randomized, Double Blind, Placebo-Controlled
Phase 1 Safety, Acceptability, and Pharmacokinetic
Study of K2B-01 Gel Administered Vaginally &
Rectally to HIV-1 Seronegative Adults
Sponsored by:
K2 BIOMEDICAL
Protocol Concept
August 11th, 2015 Version 0.2
1
PROTOCOL CONCEPT
Short Title:
K2B-01 Gel Vaginal & Rectal Safety and PK Study
Clinical Phase:
Phase 1
IND Sponsor:
K2 BIOMEDICAL
Protocol Chair:
TBD
Sample Size:
Approximately 24 evaluable participants
Study Population: HIV-uninfected men and women between the ages of 18 and 45
years (inclusive)
Participating Clinical Research Site (CRS):

TBD
Study Design:
Phase 1 randomized, double-blinded, single site, and placebocontrolled trial.
Study Duration:
Participant accrual will take approximately 4 months and each
participant will be on study for approximately 8 to 10 weeks. The
total duration of the study will be approximately 8-12 months.
Study Regimen:
The site will screen and enroll 6 participants who will receive a
single vaginal dose of K2B-01 gel. Once all six participants have
received K2B-01 gel an interim analysis will be undertaken to
assess the safety and acceptability of single vaginal dose K2B-01
gel exposure. In the absence of any safety signals the study will
proceed to the randomized placebo controlled phase of the study in
which a total of 18 participants will be randomized to receive K2B01 gel or a HEC placebo gel (K2B-01: placebo; 2:1). Each
participant will receive 1 week of daily vaginal K2B-01 gel. The first
and last dose of vaginal study product will be administered under
direct observation in the clinic. There will be a one week recovery
period between the Baseline visit and the initiation of dosing with
study product. Colposcopy and mucosal sampling will be conducted
at the Baseline Visit and at the completion of the one week dosing
period.
Following the vaginal phase of the study the site will screen and
enroll 6 participants who will receive a single rectal dose of K2B-01
gel. The participants can be individuals who complete the vaginal
2
dosing phase of the study or can be new participants. Once all six
participants have received K2B-01 gel an interim analysis will be
undertaken to assess the safety and acceptability of single rectal
dose K2B-01 gel exposure. In the absence of any safety signals
the study will proceed to the randomized placebo controlled phase
of the study in which a total of 18 participants will be randomized to
receive K2B-01 gel or a HEC placebo gel (K2B-01: placebo; 2:1).
Each participant will receive 1 week of daily rectal K2B-01 gel. The
first and last dose of rectal study product will be administered under
direct observation in the clinic. There will be a one week recovery
period between the Baseline visit and the initiation of dosing with
study product. Sigmoidoscopy and mucosal sampling will be
conducted at the Baseline Visit and at the completion of the one
week dosing period.
Study specific visits and procedures are illustrated in Figure 1 and
summarized in Tables 1 and 2.
3
:
Figure 1 Study Design
Primary Objectives:
Safety

To evaluate the safety of K2B-01
rectally
gel formulation when applied vaginally and
Acceptability

To evaluate the acceptability of K2B-01 gel when applied vaginally and rectally
4
Pharmacokinetics

To characterize the systemic and compartmental pharmacokinetics of K2B-01 gel
following vaginal & rectal application
Primary Endpoints:
Safety

Grade 2 or higher clinical and laboratory adverse events as defined by the Division
of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events,
Version 1.0, Dec 2004 and Addendum 3- Rectal Grading Table for Use in
Microbicide Studies (Clarification dated May 2012)
Acceptability

Product attributes considered likely to challenge future sustained use by participants.
Pharmacokinetics

K2B-01 concentrations
o Plasma
o Vaginal and rectal fluid
o Vaginal and rectal mucosal tissue homogenates
Secondary Objective:
Mucosal Safety

To evaluate the mucosal safety of K2B-01 gel when applied vaginally and rectally
Secondary Endpoints:





Vaginal and rectal proteomics
Vaginal and rectal transcriptome and selective RT-PCR
Vaginal and rectal microflora
Vaginal and rectal histology
Vaginal and rectal CD4+ T cell phenotype/activation
5
Exploratory Objective:
Ex Vivo Efficacy

To assess the preliminary (ex vivo) efficacy of K2B-01 gel formulation using
colorectal explants after product is applied rectally
Exploratory Endpoint:

Changes in laboratory-applied HIV-1 p-24 levels in colorectal explant supernatant
obtained from biopsies collected after K2B-01 gel application
Inclusion Criteria:
Individuals who meet the following criteria are eligible for inclusion in the study:

Age of 18 – 45 years (inclusive)

Previous history of receptive anal intercourse (RAI) in the past year

HIV-1 status antibody negative as documented at Screening and Enrollment

Understands and agrees to local STI reporting requirements

Able and willing to provide written informed consent in English to take part in the
study

Able and willing to provide adequate information for locator purposes

Availability to return for all study visits, barring unforeseen circumstances

Willing to be sexually abstinent (anal and vaginal sex) for 72 hours before and
after visits involving mucosal sampling.
Exclusion Criteria:
Individuals who meet any of the following criteria at screening will be excluded from the
study:

HIV positive at Enrollment

At screening:
o Hemoglobin < 10.0 g/dL
o Platelet count less than 100,000/mm3
o White blood cell count < 2,000 cells/mm3 or > 15,000 cells/mm3
6
o Serum creatinine > 1.3× the site laboratory upper limit of normal (ULN)
o Alanine transaminase (ALT) and/or aspartate aminotransferase (AST) >
o 2.5× the site laboratory ULN
o ≥1+ glucose or ≥1+ protein on urinalysis (UA)
History of bleeding\ problems

History of inflammatory bowel disease by participant history

Active inflammatory condition of the GI tract at baseline

Allergy to methylparaben, propylparaben, sorbic acid

Per participant report at screening, anticipated use and/or unwillingness to
abstain from the following medications during the period of study participation:
o
o
o
o
o
o
o
Heparin, including Lovenox®
Warfarin
Plavix® (clopidogrel bisulfate)
Rectally administered medications (including over-the-counter products)
Aspirin
Non-steroidal anti-inflammatory drugs (NSAIDS)
Any other drugs that are associated with increased likelihood of bleeding

By participant report at screening, use of post-exposure prophylaxis for HIV
exposure, systemic immunomodulatory medications, rectally administered
medications, rectally administered products (including condoms) containing N-9,
or any investigational products within the 4 weeks prior to the
Enrollment/Baseline Evaluation Visit and throughout study participation

Use of rectally administered medications, with the exception of over the counter
enemas, within 4 weeks of Visit 2

Use of antiretroviral PEP 4 weeks of screening.

At screening: participant-reported symptoms, and/or clinical or laboratory
diagnosis of active rectal or reproductive tract infection requiring treatment per
current CDC guidelines or symptomatic urinary tract infection (UTI). Infections
requiring treatment include symptomatic bacterial vaginosis, symptomatic vaginal
candidiasis, other vaginitis, trichomoniasis, Chlamydia (CT), gonorrhea (GC),
syphilis, active HSV lesions, chancroid, pelvic inflammatory disease, genital
sores or ulcers, cervicitis, or symptomatic genital warts requiring treatment. Note
that an HSV-1 or HSV-2 seropositive diagnosis with no active lesions is allowed,
since treatment is not required
7

Any other clinical condition or prior therapy that, in the opinion of the investigator,
would make the patient unsuitable for the study or unable to comply with the
study requirements. Such conditions may include, but are not limited to, current
or recent history of severe, progressive, or uncontrolled renal, hepatic,
hematological, gastrointestinal, endocrine, pulmonary, neurological, or cerebral
disease.
In addition to the criteria listed above, female participants must meet the following
criteria:

Postmenopausal or using (or willing to use) an acceptable form of contraception
(e.g., barrier method, IUD, hormonal contraception, surgical sterilization,
vasectomization of male partner). If the female participant has female partners
only, the method of contraception will be noted as a barrier method in the study
documentation.

Not pregnant at the Enrollment/Baseline Visit

Not breastfeeding at screening or intend to breastfeed during study participation
per participant report.
8
Table 1 Study Visit Schedule (Vaginal Dosing)
Study procedures
Informed consent
Demographics
Locator information
Test results
Behavioral questionnaire
Confirm eligibility
Reimbursement
Schedule next study visit
Randomization
Med history
Concomitant meds
Physical exam
Vaginal exam
Record/update AEs
Dipstick UA
Urine NAAT for GC/CT
HCG (females only)
CBC w/ diff and platelets
AST
ALT
Creatinine
Plasma PK levels
Syphilis RPR
HIV-1 serology
HSV-1 and -2 serology
Visit 1
Screening
Visit 2
Baseline
Week 1
X
X
X
Week 2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Visit 3
Single
Dose
Exposure
Week 4
Visit 4
Screening
(▲)
X
X
X
X
X
X
X
▲
▲
X
X
X
X
X
X
X
X
X
▲
X
X
▲
▲
X
▲
▲
▲
▲
X
▲
▲
X
X
▲
X
X
▲
▲
X
▲
X
X
▲
▲
X
▲
▲
X
▲
▲
▲
▲
▲
▲
▲
▲
▲
▲
▲
▲
▲
Visit 5
Baseline
(▲)
Visit 6
Multiple
Doses
(1-6)
Week 6
X
▲
X
X
X
X
X
X
X
▲
▲
X
▲
▲
X
▲
▲
▲
▲
▲
▲
▲
X
X
X
X
X
▲
X
X
▲
▲
X
▲
▲
▲
▲
▲
▲
Visits 7
Final
Dose
Visit 8
Telephone
Contact
Week 7
X
X
X
X
X
X
X
▲
X
X
▲
▲
X
▲
▲
▲
▲
X
▲
▲
X
9
Vaginal microflora
Colposcopy
Histology
Cervicovaginal cell
phenotype
Drug levels
 Plasma
 Cervicovaginal
tissue
 Vaginal fluid
Gene array in cervical
mucosal tissue
Proteomics in cervical
mucosal tissue
Gene array in vaginal
mucosal tissue
Proteomics in vaginal
mucosal tissue
Study product
Male condoms
Product admin phone
call each day
Safety phone call
▲= if indicated
▲
▲
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
10
Table 2 Study Visit Schedule (Rectal Dosing)
Study procedures
Informed consent
Demographics
Locator information
Test results
Behavioral
questionnaire
Confirm eligibility
Reimbursement
Schedule next study
visit
Randomization
Med history
Concomitant meds
Physical exam
Rectal exam
Record/update AEs
HIV test
Dipstick UA
Urine NAAT for GC/CT
HCG (females only)
CBC w/ diff and
platelets
AST
ALT
Creatinine
Visit 1
Screening
Visit 2
Baseline
Week 1
X
X
X
Week 2
X
X
X
Visit 3
Single
Dose
Exposure
Week 4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
▲
X
X
▲
▲
▲
X
▲
X
X
X
▲
▲
▲
Visit 4
Screening
(▲)
▲
▲
X
Visit 5
Baseline
(▲)
X
▲
Visit 6
Multiple
Doses
(1-6)
Week 6
X
Visits 7
Final
Dose
Visit 8
Telephone
Contact
Week 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
▲
X
X
▲
▲
X
▲
▲
▲
X
▲
X
X
X
▲
▲
X
▲
▲
▲
X
▲
X
X
▲
X
X
▲
▲
▲
X
▲
X
X
▲
X
X
▲
▲
▲
X
▲
▲
▲
▲
▲
▲
▲
▲
▲
▲
▲
▲
▲
▲
▲
▲
X
X
▲
X
X
▲
▲
▲
11
Plasma PK levels
Syphilis RPR
HIV-1 serology
HSV-1 and -2 serology
Rectal microflora
Flexible sigmoidoscopy
Histology
Intestinal cell
phenotype
Drug levels
 Plasma
 Rectal tissue
 Rectal fluid
Gene array in rectal
mucosal tissue
Proteomics in rectal
mucosal tissue
Intestinal explant
infection
Study product
Male condoms
Product admin phone
call each day
Safety phone call
▲= if indicated
X
X
X
X
X
▲
▲
▲
▲
▲
▲
▲
▲
▲
X
▲
▲
▲
▲
▲
X
X
X
X
▲
▲
▲
▲
X
X
X
X
X
X
X
X
▲
▲
▲
▲
X
X
X
X
X
▲
X
X
▲
X
X
X
X
X
X
X
X
X
X
X
X
X
12