A phase II, two-part, multiple-dose, dose-finding, single-blind study to investigate the safety and efficacy of ABP-700 for procedural sedation in adult patients undergoing colonoscopy

Phase I testing of ABP-700 alone and with remifentanil co-infusions in healthy
subjects have shown the ability to produce consistent dose dependent sedation
effects with conditions favorable for procedural care including minimal
involuntary muscle movement, stable hemodynamics and little respiratory
depression. When ABP-700 is given as a single-stage 30-minute continuous
infusion, a delay (> 10 minutes) was observed in the attainment of arterial
steady state plasma concentrations and stable clinical effect. Subsequent
testing showed that a dual stage *step down* infusion methodology quickly
achieved and maintained plasma concentrations required to produce a desired
clinical effect while also minimizing the peak plasma concentrations produced
during bolus administration. With these dual stage infusions, steady state
arterial plasma concentrations were attained in 3-4 minutes and thereafter
maintained steady state concentrations of approximately ± 10-15% of the target
plasma concentration over the course of a 30-minute infusion. This study aims
to test various dual stage infusion regimens which are intended to produce a
range of clinical sedation effects in order to determine their ability to
support procedural care when the procedural stimulation profile is generally
uniform and of low-moderate intensity.
To confirm the dose- and presumed effect-site concentration of ABP-700 versus
effects and adverse reaction in patients stimulated by invasive procedures,
this study will be performed in subjects undergoing routine colonoscopy with
ABP-700 dosages that replicate the range of presumed effector-site
concentrations of the phase I studies. Patients undergoing colonoscopy are
expected to demonstrate variability of tolerance to discomfort and variability
of response. Therefore the study will include administration of additional
MDCO-700 given as bolus doses when needed to ensure patient comfort and the
opportunity for completion of colonoscopy

Trial objectives
* To assess the dose-response relationship, efficacy and safety of ABP-700 for
procedural sedation in adult patients undergoing colonoscopy.
* To quantify the pharmacodynamic effect of ABP-700 including time to procedure
start, sedation depth, patient recovery and readiness for discharge
* To quantify the cardio-respiratory effects of sedation doses of ABP-700

Exploratory objectives
* To determine endoscopist and anesthesiologist satisfaction with the procedure
* To determine patient satisfaction with the procedure
* To determine patient procedural recall.
* To evaluate cognition and memory function of the patient

This is a phase II two-part, multiple dose, dose-finding, single-blind study in
adult patients undergoing elective colonoscopy for screening or diagnostic
purposes. This study is designed to test various ABP-700 infusion regimens for
rational selection of one or more dosage regimen(s) to be used for future
clinical development of ABP-700 in procedural sedation. It is also intended to
quantify pharmacodynamic effects, readiness for discharge, cognitive and memory
function, both patient and provider satisfaction, and cardio-respiratory
effects related to these dosing regimens

Patients will provide written Informed Consent prior to undergoing any protocol
related assessments or procedures, which may occur up to 14 days prior to or on
the day of the scheduled colonoscopy. The anticipated duration of the
colonoscopy is generally not expected to exceed 30 minutes.
After establishing eligibility during screening, and confirmed continued
eligibility on the day of procedure, patients will be randomized in a 1:1:1
ratio to one of three ABP-700 infusion regimens (Part 1). ABP-700 regimens are
fixed two-stage infusions. All patients will receive a concomitant remifentanil
infusion beginning 5 minutes prior to the initiation of the ABP-700. Both the
ABP-700 and the remifentanil infusions will continue until procedure
completion. Supplemental oxygen will be delivered at a rate of 2L/minute via
nasal cannula. Patients will be dosed according to their assigned regimen.
Following the initiation of ABP-700 but prior to the start of the procedure
(sedation initiation phase), patients will be evaluated for a minimum of 5 up
to a maximum of 10 minutes. During this sedation initiation phase, patients
should be calm, cooperative and without hemodynamic or tolerability issues
that, in the opinion of the anesthesiologist or endoscopist, compromise the
ability to start the procedure or patient safety. Once the provider has
established that the procedure may begin, the procedure start time will be
recorded. The start of the procedure is defined as the time of the digital
rectal examination (DRE) or colonoscope insertion whichever comes first. During
the sedation initiation phase, no other medications except the ongoing
infusions of ABP-700 and remifentanil should be given. Dose adjustments should
not be made during this time.
If at the end of the maximum10-minute sedation initiation period, the patient
is without hemodynamic or tolerability issues, the procedure should begin. If a
decision is made not to proceed with the assigned regimen, the reason(s) will
be recorded and rescue midazolam may be administered in order to achieve
adequate sedation and start the procedure. ABP-700 infusion will continue
unless the decision to give rescue midazolam is due to safety or tolerability
issues. If ABP-700 is discontinued, the patient will also immediately receive
rescue midazolam. The procedure will then be completed using institutional
Standard of Care. The day of procedure and follow-up assessments will be
completed in these treatment failure patients.
ABP-700 will be maintained according to the assigned dosing regimen for the
duration of the procedure. After the start of the procedure, up to 2
supplemental ABP-700 bolus doses of 50 µg/kg are allowed at the discretion of
the anesthesia provider to maintain conditions acceptable for procedure
completion. These supplemental bolus doses can occur no more frequently than
every 5 minutes with no more than 2 boluses allowed. If adequate sedation
conditions cannot be maintained using supplemental ABP-700 doses, the
anesthesiologist can administer alternative rescue midazolam as needed.
BIS and MOAA/S scores will be recorded beginning at least 1 minute prior to the
start of remifentanil co-administration and will continue until the patient is
considered fully recovered.
After the procedure has ended and the infusions have stopped, a patient is
considered fully recovered once he/she has both a BIS > 70 and 3 consecutive
MOAA/S scores of 5, each scored 1 minute apart. Within 15 minutes after full
recovery, the patient, the anesthesiologist and the endoscopist will complete
patient and clinical satisfaction instruments to determine satisfaction with
the procedure.
Patients will subsequently be transferred to a recovery area for further
evaluations until they are determined ready for discharge. Procedural recall
will be measured by the Modified Brice questionnaire. Patient recovery will be
assessed using the Modified Aldrete (APRS) recovery scoring system. Cognitive
recovery will be measured using the cognitive domain of the Post-operative
Quality Recovery Scale (PQRS).
Patients will be contacted by phone after 5-7 days for a follow-up.

Although respiratory status remains generally well preserved after both bolus
dosing (ANVN-01 and ANVN-03) and infusion dosing (ANVN-02 and ANVN-01-04), both
self limited episodes of respiratory depression and apnea have been reported
with ABP-700. In the presence of co-infusions of remifentanil, apnea
necessitating provider intervention has been reported.
Transient skeletal muscle contractions or IMM (i.e., muscle twitching and
myoclonus) has also been observed with ABP-700. Low doses of fentanyl,
midazolam or a combination of fentanyl and midazolam are effective at
attenuating or eliminating these movements. Midazolam (0.015 mg/kg to 0.03
mg/kg) was effective in rapidly stopping (approximately 30 sec to 90 sec) any
ABP-700-induced severe IMM.
IMM, ranging from mild twitching of the face, torso, and/or limbs to more
extensive flexor/extensor jerking movements of the limbs (i.e., myoclonus) has
been observed with ABP-700. In general, IMM was dose dependent, occurring with
higher frequency and severity with higher doses. Pre-treatment with either
fentanyl or midazolam or a combination of midazolam plus fentanyl decreased the
frequency and severity of IMM following bolus dosing of ABP-700. Fentanyl
pre-treatment and remifentanil co-infusion decreased the frequency and severity
of IMM following infusion dosing of ABP-700.
Airway patency and airway reflexes were preserved with ABP-700 and ABP-700 was
not associated with clinically meaningful respiratory depression (i.e., oxygen
saturation decrease or intervention required). Respiratory stability was also
maintained when ABP-700 was dosed following pre-treatment with either an
opiate, benzodiazepine, or combination of an opiate and benzodiazepine.
Infrequent, short-lived and self-limited episodes of respiratory depression
were seen with ABP-700 bolus dosing with these pre-treatments.
Apnea necessitating provider intervention (i.e., chin lift, jaw thrust,
positive pressure mask ventilation) was seen with ABP-700 bolus dosing,
infusion dosing, and infusion dosing in the presence of a continuous
remifentanil co-infusion (0.05 *g/kg/min and 0.5 *g/kg/min).
Nausea has been reported with ABP-700 and was seen more frequently in subjects
who received remifentanil either as a pre-treatment or a co-infusion. Nausea
has been self-limited and a single dose of an anti-emetic (i.e., ondansetron),
when treatment was required, has been effective at amelioration.
Mild injection/infusion site reactions at the site of administration have been
observed with ABP-700.