The primary objective is to evaluate the efficacy and safety of NTRA-9620 compared with placebo when added to standard of care (SOC) in pediatric subjects (aged 28 weeks post-menstrual age to 52 weeks chronological age) with SBS within 4 months from…
ID
Source
Brief title
Condition
- Malabsorption conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoints are the percent changes in %PN (PC_PN0-t) from baseline
based on caloric intake to 12 weeks and again to 24 weeks. Each endpoint is
calculated as:
*PC_PN*_(0-t)=100×(*%PN*_Baseline-*%PN*_t)/*%PN*_Baseline
where:
t = 12 or 24weeks.
%PN = % Parenteral Nutrition (feeding) calculated as parenteral calories
divided by calculated total caloric requirements (the Schofield equation ).
Each *PC_PN*_(0-t) observation will be computed as an average over a
single week.
Thus, for example, PC_PN at 12 weeks will be the average of PC_PN over
days 78 to 84.
PC _PN at 24 weeks will be the average of PC_PN over days 162 to 168.
The study will have shown benefit if either PC_PN0-12 or PC_PN0-24 in the
treated group is statistically significantly superior to placebo.
Secondary outcome
Key Secondary Endpoint
Time to reduction of PN to less than 10% of the total caloric intake on 14
consecutive days.
Other Secondary Endpoints
a) Time to wean off parenteral nutrition
b) Number of patients reaching readiness to wean off at 12 and 24 weeks from
baseline.
c) Time to 50% PN/IV reduction from baseline in %PN based on total calories.
d) Time to 50% PN/IV reduction from baseline in %PN based on volume.
e) Number of patients reaching 50% PN/IV reduction from baseline in %PN based
on total calories at 12 and 24 weeks.
f) Number of patients reaching 50% PN/IV reduction from baseline in %PN based
on volume at 12 and 24 weeks.
g) Percent change from baseline in %PN/IV based on total calories.
h) Percent change from baseline in %PN/IV based on volume.
i) Percent change from baseline in PN/IV fluid volume during treatment period.
j) Change in Z-scores (Fenton) from baseline during the treatment period
k) Percent change from baseline in %EN based on total calories.
l) Percent change from baseline in %EN based on total volume.
m) Change from baseline in liver enzymes (ALT, GGT, and total and direct
bilirubin).
n) Change from baseline in plasma citrulline levels.
o) Change from baseline in body weight during the treatment period.
p) Weekly average of hours on prescribed PN/IV during the last month of
treatment.
q) General safety variables including episodes of significant feeding
intolerance
compared to placebo.
Background summary
The majority of the target population consists of preterm and term infants
suffering from conditions soon after birth that result in the loss of or damage
to the small bowel. Given that the natural development and maturation of the
intestine occurs during the third trimester and first year of life, the
additional insult of bowel loss at this critical period of time makes this
group a high risk population for prolonged intestinal failure requiring
potentially lifelong parenteral nutrition (PN). All infants in this group of
patients require PN post-operatively. Early enteral (EN) feeding should be
promoted as soon as possible to enhance gastrointestinal (GI) maturation,
growth and functional development. Infants should be weaned off PN as enteral
tolerance to feeding is enhanced (2).
Intestinal failure in the context of Short Bowel Syndrome (SBS) is associated
with dependency on PN for a prolonged period of time. Evidence suggests that
the survival rate after massive small bowel resection depends on the ability of
the residual bowel to adapt while decreasing the probability of PN associated
co-morbidities. Moreover, successful adaptation allows patients with SBS to
grow and remain healthy while receiving oral nutrition or EN. As indicated,
the most important therapy for children with SBS is the early introduction of
EN.
Insulin, which plays a role in intestinal growth, cell maturation, and
differentiation, has been shown to enhance intestinal adaptation. Nutrinia is
developing an insulin formulation, NTRA 9620, to enhance EN intake in infants
with SBS following surgical resection. NTRA 9620 is an oral insulin
formulation for local GI therapy aimed at accelerating the natural course of
intestinal adaption and maturation.
NTRA-9620 is an oral formulation of insulin for local GI therapy without
systemic insulin exposure aimed at increasing intestinal adaption.
Evidence supports the fact that intestinal adaptation is enhanced and sustained
when growth factors are provided immediately following intestinal loss (3).
This adaptation is likely to be further augmented when growth factors are
administered during early development, the most critical period of gut growth.
The dual effects of NTRA-9620 to enhance both adaptation and enteral tolerance
at this vital time are major strengths of the product concept.
Benefits of accelerating adaptation over placebo in this proposed responder
definition that can be translated to an average of 2-3 fewer hours a day
*attached* to PN, which is associated with the following:
1. Insulin*s receptor-mediated structural effects on the GI tract such as
increased rate of enterocyte proliferation, villous height, and crypt depth
that leads to better gut adaptation (4).
2. Adequate enteral nutrients absorption for supporting the infant's growth and
development, and, in the long-term, improved nutrition early in life that leads
to better growth and development has been linked to overall improved health
outcomes in this population (2).
3. Minimizing exposure to toxic constituents such as lipids and dextrose which
may result in less metabolic stress on the growing infant (5).
4. Reduction of PN-associated co-morbidities such as parenteral
nutrition-associated liver disease (PNALD), bacterial overgrowth,
catheter-associated bloodstream infections, cholestatic liver disease, and
death (6, 7).
5. As PN/IV requirements decrease, this can potentially be translated to an
opportunity to advance cycling of PN/IV. This is an important opportunity to
introduce oral rehabilitation strategies during the daytime awake hours and
then provide the remaining PN/IV support overnight for example.
6. Less opportunities of necessity to handle fragile central line access that
may predispose to infection or malfunction (8).
7. Increased oral stimulation to feed, EGF secretion leading to gut development
and reduced malnutrition, thus enhanced growth and associated development
8. Increased hours of normal development behavior as a child grows without
being *attached* or connected to a line (9, 10).
9. Less hours of necessary specialized supervision, which reduce the costs and
provides support in parents.
Therefore, acceleration in the reduction in the percent PN and enhancement of
EN intake during this period of gut adaptation is hypothesized to be the most
appropriate method to assess progress towards full enteral autonomy, even if
the latter takes years to achieve.
Study objective
The primary objective is to evaluate the efficacy and safety of NTRA-9620
compared with placebo when added to standard of care (SOC) in pediatric
subjects (aged 28 weeks post-menstrual age to 52 weeks chronological age) with
SBS within 4 months from surgical resection who are on parenteral nutrition
(PN) support.
Study design
This multi-center, randomized, double-blind, three-arm, parallel-group trial is
designed to assess the efficacy and safety of two doses (8 IU/kg/day and 4
IU/kg/day) of NTRA-9620 or matching placebo at two time points (12 and 24 weeks
post randomization) administered to infants less than 52 weeks chronological
age with SBS (following surgical resection). The study will be conducted in
approximately 40 clinical trial sites worldwide. Subjects will continue on SOC
nutrition after the 24 week intervention period. A final study visit will be
conducted at Week 28, 4 weeks after the end of dosing. All subjects will be
further followed for long-term safety through Week 104; these safety data will
be reported as an addendum to the final clinical study report
Intervention
All three groups will receive NTRA-9620 or matching placebo four times per day
for 24 weeks.
Group 1: NTRA-9620 2 IU/kg for each dose (8 IU/kg per day).
Group 2: NTRA-9620 1 IU/kg for each dose (4 IU/kg per day).
Group 3: Matching placebo for each dose.
Study burden and risks
Except for the risks mentioned in E9, no other risks are foreseen. The
additional burden compared to the standard of care is minimal.
6 HA-Khilazon Street /
Ramat-Gan 5252270
IL
6 HA-Khilazon Street /
Ramat-Gan 5252270
IL
Listed location countries
Age
Inclusion criteria
Subjects must meet all of the following criteria to be included:
1) Subject must be at least 28 weeks post-menstrual age and up to 52 weeks chronological age at enrollment.
2) Subject weight must be at least 500 grams (17.6 ounces) at time of enrollment.
3) Clinically diagnosed with SBS requiring PN/IV secondary to surgical resection of the intestine.
4) After major surgical resection leading to SBS, the subject has maximally 70% of expected bowel length preserved or an ostomy in place such that * 70% of the small bowel is available for absorption .
5) Subject can tolerate at least 10 mL/kg/day of enteral nutrition (EN) for at least 7 days at time of enrollment.
6) At time of enrollment subject is on at least 70% of prescribed PN/IV and no more than 30% of EN based on total caloric intake for at least 7 days prior to study entry.
7) Subject is randomized into the trial within 4 months from the surgical resection that has led to the diagnosis of SBS.
8) Subject*s parent(s) or legal guardian(s) provide written informed consent.
9) Subject*s parent(s) or legal guardian(s) understand and are willing to comply with all study procedures and requirements.
Exclusion criteria
Subjects meeting any of the following criteria at study entry will be excluded:
1) Subject has undergone any bowel lengthening procedure.
2) Subject has a malabsorption disorder such as:
* Congenital etiology (such as microvilli inclusion disease, tufting enteropathy)
* Untreated Hirchsprung*s disease
3) Significant motility disorder such as:
* Pseudo obstruction
* Severe gastroschisis defined as: primary reason for PN support is due to persistent feeding intolerance of less than 20 ml/kg/day EN intake or signs and symptoms (i.e., abdominal distention, vomiting) requiring prokinetic agents.
4) Any known inherited abnormality (e.g., Fanconi syndrome,) that is not related to SBS.
5) Prior bowel resection due to isolated spontaneous intestinal perforation.
6) < 10 cm of remaining small bowel left with no colon.
7) Uncontrolled systemic infection, acute gastroenteritis, pneumonia, cardiovascular or other abnormality including EKG findings that in the opinion of the investigator makes the infant unstable and at significant risk of not completing the first 12 weeks of the study.
8) Subjects with known hyperinsulinemia .
9) Subjects with unexplained or recurrent hypoglycemia with blood glucose * 50 mg/dL within 48 hours of treatment initiation.
10) Subjects with severe anemia of Hemoglobin less than 60 g/L and requiring transfusion within 48 hours of treatment initiation to avoid a life threatening event.
11) Subjects who require pancreatic enzyme replacement therapy.
12) Subject is currently receiving oral or injectable insulin for any reason.
13) Participation in another interventional clinical study within the past 30 days that may interfere with the results of this study.
14) History or current use of growth factors or glutamine.
15) In the opinion of the investigator, the subject has any other medical condition that would make participation in this study either unsafe or would compromise the potential benefit of insulin treatment
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-000181-60-NL |
| ClinicalTrials.gov | NCT02865122 |
| CCMO | NL60431.018.17 |