![](media/image1.png)

[Department of Health and Human Services]{.smallcaps}

[Food and Drug Administration]{.smallcaps}

[Center for Drug Evaluation and Research]{.smallcaps}

[Office of Biostatistics]{.smallcaps}

Statistical Review and Evaluation

clinical studies

  ----------------------- -----------------------------------------------
  NDA:                    21-597

  Name of drug:           Serostim^®^ \[somatropin (rDNA origin) for
                          injection\]

  Applicant:              Sereno Laboratories, Inc.

  Indication:             Treatment of short bowel syndrome

  Documents reviewed:     Vol. 1-8 dated 10/31/02

  Project manager:        Alice Kacuba (HFD-180)

  Clinical reviewer:      Hugo Gallo-Torres, M.D. (HFD-180)

  Dates:                  Received 10/31/02; user fee (10 months)
                          09/01/03

  Statistical reviewer:   Dionne L. Price, Ph.D. (HFD-715)

  Statistics team leader: J. Todd Sahlroot, Ph.D. (HFD-715)

  Biometrics division     S. Edward Nevius. Ph.D. (HFD-715)
  director:               

                          

  Keywords:               NDA review, clinical studies, analysis of
                          covariance
  ----------------------- -----------------------------------------------

1 Executive Summary of Statistical Findings
[0](#executive-summary-of-statistical-findings)

1.1 Conclusions and Recommendations
[0](#conclusions-and-recommendations)

1.2 Overview of Clinical Program and Studies Reviewed
[0](#overview-of-clinical-program-and-studies-reviewed)

1.3 Principal Findings [0](#principal-findings)

2 Statistical Review and Evaluation of Evidence
[0](#statistical-review-and-evaluation-of-evidence)

2.1 Introduction and Background [0](#introduction-and-background)

2.2 Data Analyzed and Sources [0](#data-analyzed-and-sources)

2.3 Statistical Evaluation of Evidence on Efficacy / Safety
[0](#statistical-evaluation-of-evidence-on-efficacy-safety)

2.3.1 Sponsor\'s Results and Conclusions
[0](#sponsors-results-and-conclusions)

2.3.2 Statistical Methodologies [0](#statistical-methodologies)

2.3.3 Detailed Review of Individual Studies
[0](#detailed-review-of-individual-studies)

2.3.4 Statistical Reviewer's Findings
[0](#statistical-reviewers-findings)

2.4 Findings in Special/Subgroup Populations
[0](#findings-in-specialsubgroup-populations)

2.5 Conclusions and Recommendations
[0](#conclusions-and-recommendations-1)

2.6 Labelling [0](#labelling)

2.7 Appendix [0](#appendix)

# Executive Summary of Statistical Findings

## Conclusions and Recommendations

Sereno Laboratories, Incorporated has proposed Serostim^®^, a
recombinant human growth hormone (rhGH), for the improvement of residual
gut absorptive function in patients with short bowel syndrome (SBS). A
primary claim of the sponsor is that rhGH, administered singly and as
cotherapy with glutamine, reduces the total intravenous parenteral
nutrition (IPN) volume requirements of SBS patients. The evidence taken
from the reviewed study indicates statistical support favoring
Serostim^®^ for the treatment of short bowel syndrome. Additional claims
are made regarding IPN calorie content and frequency of IPN
administration. Evidence further suggests that Serostim^®^ significantly
reduces both IPN calorie content and frequency of administration among
SBS patients.

Of note, all study participants received an oral diet individualized to
meet nutritional needs. Moreover, modifications to the diet throughout
the treatment period were necessary to maintain adequate nutritional
status. Due to the daily changes to the diet after randomization and the
potentially complex relationship between diet and total IPN volume, an
unbiased statistical analysis of total IPN volume adjusting for the
effect of diet is not possible. However, summary data on the diet and
nutritional status of patients are included in the review to provide
clinicians with a descriptive clarification of the nature and strength
of the relationship between diet and IPN utilization over time.

## Overview of Clinical Program and Studies Reviewed

*Background*

Serostim^®^, as a drug product for the treatment of SBS, was introduced
to the Food and Drug Administration via IND 48,570. The clinical
development plan was discussed via several meetings, telephone
conferences, and correspondences. Discussion topics included the
appropriateness of a single study to establish efficacy, the
appropriateness of various clinically defined outcomes, and the
potential for confounding via the specialized oral diet individually
formulated for each patient. The present submission contains a single,
randomized, double-blind study designed to investigate the safety and
efficacy of Serostim^®^ for the proposed indication.

*Study Design*

Intravenous parenteral nutrition-dependent subjects diagnosed with SBS
were entered into a two-week baseline period. During this period, each
subject's IPN requirements were stabilized, and subjects began an oral
diet specifically formulated for each subject, individually. Following
baseline assessments, forty-one patients were randomized to rhGH, rhGH
and glutamine in cotherapy, or glutamine in a 2:2:1 ratio, respectively.
During the four-week treatment duration, each subject's IPN was reduced
according to a prespecified reduction scheme.

*Statistical Analyses*

In Study IMP20317, the primary measure of efficacy was the change in
total volume of IPN from week 2 to week 6. "Total volume was defined as
the sum of the volumes of IPN, supplemental lipid emulsion (SLE), and
intravenous hydration fluid administered each week. " The primary
outcome was analyzed utilizing an analysis of covariance model with
baseline covariate. Pairwise comparisons between both rhGH treatment
groups and glutamine were assessed utilizing Dunnett-Hsu test to control
the Type I error rate at 5%.

The sponsor also identified two secondary measures of efficacy namely,
the change in total IPN calories and the change in IPN frequency from
baseline to the end of treatment. The two variables were analyzed
similarly to the primary efficacy variable.

*Sponsor's Results and Conclusions*

In Study IMP20317, a statistically significant reduction in total IPN
volume was achieved by patients receiving rhGH, singly or as cotherapy
with glutamine, as compared to patients receiving only a specialized
oral diet supplemented with glutamine. Moreover, patients in the rhGH
groups achieved significant reductions in IPN caloric content and IPN
administration frequency.

## Principal Findings

Following my evaluation of the study, I conclude that Serostim^®^,
administered singly or as cotherapy with glutamine, reduces the total
IPN requirement of patients with short bowel syndrome. Specifically in
the evaluated study, there exists a decrease in IPN utilization over the
treatment duration of 3.8L, 7.7L, and 5.9L among the glutamine, rhGH and
glutamine cotherapy, and the rhGH groups, respectively. Moreover, the
drug product also produces significant reductions in weekly IPN calorie
content and the frequency of IPN administration.

All patients in study IMP20317 received a specialized oral diet tailored
to the individual nutritional needs of patients. As stated by the
sponsor, " The objective of the diet is to ensure that each subject is
able to maintain through oral feeding, adequate nutritional status,
which can promote nutrient absorption and independence from IPN
following discharge from the clinic." Summary data suggested an increase
in the components of the oral diet from week 2 to week 6 across each
treatment group. With the exception of the oral fluid component, larger
increases in the intake of the quantified components of the oral diet
were evident for the cotherapy group as compared to the glutamine group.
Thus, the greater reduction in total IPN requirements observed in the
cotherapy group was accompanied by a greater increase in the specialized
oral diet.

Additional issues deferred to the medical review of Dr. Hugo
Gallo-Torres include the clinical significance of the rhGH effect, the
appropriateness of the endpoints, and the appropriateness of a single
study for the proposed indication.

# Statistical Review and Evaluation of Evidence 

## Introduction and Background

Serostim^®^ is a recombinant human growth hormone (rhGH) currently
approved in the United States for the treatment of AIDS wasting or
cachexia. Serostim^®^ was originally evaluated for the aforementioned
indication via adequate and well-controlled studies contained in NDA
20-604. Serono Laboratories, Inc. submitted the current application (NDA
21-597) on 31 October 2002. The present submission investigates the
safety and efficacy of rhGH (singly and as cotherapy with glutamine) for
the treatment of short bowel syndrome via a randomized, double-blind
study.

The drug product for the proposed indication was initially introduced to
the Food and Drug Administration via IND 48,750 submitted by Sereno
Laboratories, Inc. on    31 August 1995. The IND protocol outlined Study
GH-003. The study was also conducted under IND 58,284 submitted on 9
October 1997 by a second sponsor.

The clinical development plan was the subject of several meetings,
telephone conferences, and correspondences between the Division of
Metabolism and Endocrine Drug Products and the companies. Issues
addressed included the appropriateness of one single center study to
establish efficacy, the appropriateness of various clinically defined
outcomes, and the potential for confounding via the proposed specialized
oral diet individually formulated for each patient. Of note, the current
NDA was transferred from the Division of Metabolism and Endocrine Drug
Products to the Division of Gastrointestinal and Coagulant Drug Products
shortly after submission.

## Data Analyzed and Sources

The sponsor provided Study IMP20317 (previously referenced as Study
GH-003) in support of the proposed indication. I reviewed volumes 1-8 of
NDA 21-597 dated 31 October 2002. The data were archived in the Food and
Drug Administration internal document room under the network path
location,
   [\\\\CDESUB1\\N20604\\S_026\\2002-10-31](../../../../../../../../N20604/S_026/2002-10-31).
Upon initial investigation of the data, I discovered that definitions of
the variables were not provided. The division requested the data
definition tables, and Sereno Laboratories, Inc. submitted the tables on
14 February 2003.

Study IMP20317 was a double-blind, phase 3, controlled study conducted
in the United States. Forty-one patients were randomized to rhGH,
glutamine, or a cotherapy of rhGH and glutamine in a 2:2:1 ratio,
respectively.

## Statistical Evaluation of Evidence on Efficacy / Safety

Intravenous parenteral nutrition (IPN) dependent subjects diagnosed with
short bowel syndrome (SBS) were entered into a two-week baseline period.
During this period, each subject's IPN requirements were stabilized, and
subjects began a specialized oral diet (SOD) specifically formulated for
the individual subject. The specialized oral diet, as outlined in the
protocol, is provided in the Appendix. Following baseline assessments,
eligible subjects were randomized to treatment for a four-week duration.
Patients received one of the three following treatment regimes: 0.10
mg/kg/d subcutaneous rhGH and a SOD supplemented with 27 g/d of oral
glutamine placebo, 0.10 mg/kg/d subcutaneous rhGH and a SOD supplemented
with 30 mg/d oral glutamine, or 0.10 mg/kg/d subcutaneous rhGH placebo
and a SOD supplemented with 30 mg/d oral glutamine. Glutamine
supplements were dispensed in packets, and patients mixed the packet
contents with water or Crystal Light^®^ beverage. During the treatment
duration, each subject's IPN was reduced according to a prespecified
reduction scheme (in Appendix).

The proposed objective of IMP20317 was to evaluate the change in total
intravenous parenteral nutrition (IPN) requirements measured from
baseline to the end of treatment.

### Sponsor\'s Results and Conclusions

In Study IMP20317, a statistically significant reduction in total IPN
volume was achieved by patients receiving rhGH, singly or as cotherapy
with glutamine, as compared to patients receiving only a specialized
oral diet supplemented with glutamine. Moreover, patients receiving
rhGH, singly or as cotherapy with glutamine, achieved significant
reductions in IPN caloric content and IPN administration frequency.

### Statistical Methodologies

The primary measure of efficacy was the change in total volume of IPN
from Week 2 to Week 6. " Total volume was defined as the sum of the
volumes of IPN, supplemental lipid emulsion (SLE), and intravenous
hydration fluid administered each week. " The sponsor identified two
secondary measures of efficacy, namely, the change in total IPN calories
and the change in IPN frequency from baseline to the end of treatment. "
Total calories were defined as the sum of kilocalories for carbohydrate,
protein , and fat in the IPN and SLE administered each week and the
kilocalories in the intravenous hydration fluid. " IPN frequency was
calculated using the number of days per week of administration of IPN.
If no intravenous parenteral nutrition was administered, IPN frequency
was defined as the number of days per week of administration of SLE
provided the amount of SLE was greater than 200 kilocalories.

The primary efficacy endpoint was analyzed via an analysis of covariance
(ANCOVA) model with baseline measurement as a covariate. Primary
analyses focused on assessing treatment group differences among rhGH
(singly or as a cotherapy with glutamine) and glutamine alone. The
sponsor referenced the specialized oral diet supplemented with glutamine
as SOD\[GLN\], and similarly referenced the specialized oral diet
supplemented with placebo as SOD. Utilizing these references, the
sponsor stated, "Since treatment with SOD\[GLN\] was not expected to
alter IPN requirements, this study compared treatment with rhGH +
SOD\[GLN\] to treatment with SOD\[GLN\] alone and treatment with
rhGH+SOD to treatment with SOD\[GLN\] alone." The two pairwise
comparisons of interest were examined via the Dunnett-Hsu test to
control the type I error rate at 5%. The aforementioned analysis plan
was also followed for the secondary variables of interest.

### Detailed Review of Individual Studies

The sponsor enrolled 41 patients across two sites in the United States.
Of note, only three patients were enrolled at the second site, the
University of Nebraska (Omaha). The primary site was the Nutritional
Restart Center, a "referral center for patients with severe
malabsorptive disorders." The sample size was based on a previous study
by Byrne et al.[^1] and was adequate to provide 80% power to detect a
6.6 L per week difference in IPN volume between each rhGH group and
glutamine group (assuming a root mean square error of 5.5L per week).
Primary analyses were performed on the intent to treat population
consisting of all randomized patients. Additionally, the sponsor
performed analyses on the efficacy evaluable population and a treatment
responder population. The efficacy evaluable population included all
patients who completed the study according to specified criteria. The
treatment responder population included subjects who demonstrated a 100%
reduction in total IPN volume. The latter two populations were not of
focus in my review.

Approximately 71% of study participants were female, and the majority of
study participants were Caucasian. The ages of subjects were between 20
and 75 with a mean age of 50 years (standard deviation of 15.6). Weight,
number of years since most recent bowel resection, length of residual
jejunum-ileum, percent of intact colon, and IPN history ( frequency,
volume, and calories) were evaluated as additional baseline
characteristics. There were no statistically significant differences
between treatment arms regarding demographic or the baseline
characteristics. A summary of demographic variables and baseline
characteristics is provided in the Appendix.

Of the 41 randomized study participants, 16 subjects were randomized to
the rhGH arm, 16 subjects were randomized to the rhGH and glutamine
cotherapy arm, and 9 subjects were randomized to the glutamine only arm.
An individual in the rhGH treatment group did not complete the study due
to an adverse event. Due to the small number of patients with missing
efficacy data, concerns regarding the statistical methodology utilized
to handle missing data are minimized. However, the sponsor did
pre-specify methodology to be utilized for missing data. According to
the sponsor, missing baseline values were imputed via the mean observed
baseline value for all subjects. Similarly, the mean observed change
from baseline for a given wee was calculated and added to the baseline
value for a patient missing a post-baseline value. In addition, the data
were analyzed using a last observation carried forward (LOCF) strategy
as well as a mixed model repeated measures (MMRM) strategy.

Table 1 depicts the results of the sponsor's analyses performed on the
primary and secondary variables. Results for the efficacy variables are
generated via methodology outlined in Section 2.3.2 with missing data
handled via the sponsor's prespecified proposal. Models initially
included a term for a baseline by treatment interaction. The interaction
term was significant in the analysis of the primary efficacy variable;
therefore, it was retained in the model. The interaction term was not
significant in the analyses of the secondary variables; therefore,
analysis models of secondary variables were run without the interaction
term.

**Table 1** Summary of change in Total IPN Volume, Calories, and
Frequency from Week 2 to Week 6 for ITT Population by Treatment Group
(as presented by sponsor)

+------------------+-----------+-----+-------------+------+-----------+
| Endpoints        | rhGH      | p   | rhGH + GLN  | p-v  | GLN       |
|                  |           | -va |             | alue |           |
|                  | (N=16)    | lue | (N=16)      |      | (N=9)     |
+------------------+-----------+-----+-------------+------+-----------+
| Mean change in   | -5.9      | 0   | -7.7(3.2)   | \    | -3.8(2.4) |
| total IPN volume | (3.8)     | .04 |             | <0.0 |           |
| \[L/wk\] (std    |           | 3\* |             | 01\* |           |
| deviation)       |           |     |             |      |           |
+------------------+-----------+-----+-------------+------+-----------+
| Mean Change in   | -4338.    | 0.  | -575        | \<   | -2633.    |
| Total IPN        | 3(1858.4) | 005 | 1.2(2081.9) | 0.00 | 3(1340.5) |
| Calories         |           | ^†^ |             | 1^†^ |           |
| \[kcal/wk\]      |           |     |             |      |           |
| (Std. Dev)       |           |     |             |      |           |
+------------------+-----------+-----+-------------+------+-----------+
| Mean Change in   | -         | 0.  | -4.2(1.4)   | \<   | -2.0(0.9) |
| IPN or SLE       | 3.0(1.98) | 025 |             | 0.00 |           |
| Frequency        |           | ^†^ |             | 1^†^ |           |
| \[d/wk\] (Std.   |           |     |             |      |           |
| Deviation)       |           |     |             |      |           |
+------------------+-----------+-----+-------------+------+-----------+

\* P-values were determined from pairwise comparisons of treatment
groups with the GLN treatment group by using Dunnett-Hsu t-test
following ANCOVA with Week 2 as covariate including baseline by
treatment interaction.

† P-values were determined from pairwise comparisons of treatment groups
with the GLN treatment group by using Dunnett-Hsu t-test after ANCOVA
with Week 2 as covariate.

**Figure 1:**

![](media/image2.wmf)

The results in Table 1 demonstrated significant differences in the mean
changes in total IPN volume, calories, and frequency between groups. I
additionally generated Figure 1 to further illustrate differences in the
mean total IPN volume at week 2 and week 6 among the three treatment
groups. A reduction in IPN utilization among patients receiving rhGH and
the cotherapy composed of rhGH and glutamine was demonstrated in the
study. The reduction in IPN utilization among patients receiving rhGH
and glutamine in cotherapy was highly significant as compared to
patients receiving glutamine alone suggesting a rhGH effect. A
borderline significant reduction in IPN utilization was also noted in
the rhGH (alone) group in comparison to the glutamine group. There
existed a decrease in IPN utilization over the treatment duration (week
2 to week 6) of 3.8 L, 7.7 L and 5.9 L among the glutamine, rhGH and
glutamine cotherapy, and rhGH alone groups, respectively. Additionally,
highly significant reductions in IPN calories and frequency from week 2
to week 6 were evident from results displayed in Table 1.

With regards to the primary efficacy variable, I reanalyzed the data
provided applying the same methodology and am in agreement with the
sponsor's statistical results and conclusions as summarized in Section
2.3.1. Moreover, the results are very similar when utilizing LOCF and
MMRM to handle missing data. Of note, a statistically significant
baseline by interaction term was found in the analysis of the primary
efficacy variable. The analysis is not invalidated by the apparent
interaction; however, some caution is warranted in interpretation.
Insight into the differential treatment effects across baseline IPN
volume increases understanding thus aiding in an appropriate
interpretation. The sponsor further reported results by using the
estimated quartiles of the baseline as shown in Table 2. Based on Table
2, the sponsor concludes that subjects with higher baseline IPN
requirements experience greater treatment effects as compared to
subjects with lower IPN requirements at baseline.

Table 2: Baseline quartile results for mean change in total IPN

  ---------------- -------------- ----------- -------------- ----------- ------------
                   rhGH +SOD      p-value\*   rhGH +         p-value\*   SOD\[GLN\]
                                              SOD\[GLN\]                 

  First quartile   -4.55 (0.64)   0.832       -5.77 (0.68)   0.229       -4.00 (0.97)
  (7.50)                                                                 

  Second quartile  -5.94 (0.57)   0.083       -7.75 (0.56)   0.001       -3.92 (0.81)
  (10.50)                                                                

  Third quartile   -7.74 (0.71)   0.001       -10.32 (0.76)  0.001       -3.81 (0.76)
  (14.40)                                                                
  ---------------- -------------- ----------- -------------- ----------- ------------

\* P-values were determined from pairwise comparisons of treatment
groups with the SOD\[GLN\] treatment group by using Dunnett Hsu t-test
following ANCOVA. Means shown are LS-Means computed at the respective
quartile values.

Analysis of the secondary variables, change in total IPN calories and
change in IPN frequency, demonstrated further support of a statistically
significant difference between rhGH (singly or as cotherapy) and a
specialized oral diet supplemented with glutamine. Specifically, a
statistical difference exists between the pairwise comparisons of
interest, namely, rhGH as compared to glutamine alone and rhGH in
cotherapy with glutamine as compared to glutamine alone.

Additional analyses outlined by the sponsor included an examination of
the IPN requirements during the follow-up period (Week 6 to Week 18) and
the effect of covariates. Pre-specified covariates that were
individually assessed by the sponsor included age, sex, race, baseline
weight, time since last resection, length of residual jejunum-ileum,
presence of an intact colon, and IPN history. The protocol specified
that continuous covariates would be examined via the Type I sums of
squares. In consultation with the medical officer, Dr. Hugo
Gallo-Torres, three covariates of particular interest were identified,
namely weight, presence of an intact colon, and length of residual
jejunum-ileum. Based on the results from the specified analysis, the
sponsor concludes that the presence of an intact colon did not
significantly influence the total IPN volume. However, the baseline
weight and length of residual jejunum-ileum covariates were significant
when added to the model. Moreover analyses with both covariates provided
further support of the significant difference between the cotherapy of
rhGH and glutamine as compared to glutamine alone.

I briefly evaluated the sponsor's analysis of the follow-up period. In
particular, I investigated the analysis of the IPN volume utilizing an
ANCOVA model with week 2 as a baseline covariate. Interest focused on
observed differences in the change in IPN volume from baseline to week
18. Of note, the efficacy variable in the analysis was total IPN volume
excluding the SLE and hydration components as those components were not
measured during the follow-up period. Results indicate a significant
reduction in IPN utilization among the cotherapy (rhGH and glutamine)
group as compared to the glutamine only group. The results suggest that
four weeks of treatment is sufficient to maintain the reduction in IPN
utilization for a period of twelve weeks. The same significance was not
achieved when comparing the rhGH group to the glutamine only group.

In addition to the review and verification of the sponsor's primary and
secondary analyses, I also examined relationships of potential interest.
The sponsor primarily focused on the total IPN volume defined as the sum
of three components, namely, IPN, SLE, and hydration fluid. After an
exploratory investigation, I determined that the IPN component had the
greatest contribution to the total volume. Approximately 71 % of the
total IPN volume calculations from week 2 and week 6 were equivalent to
the IPN volume component. Moreover, I applied the same methodology as
used in the analysis of the primary efficacy variable to the IPN
component (excluding SLE and hydration fluids). The results also
indicate a statistically significant difference between rhGH as compared
to a diet supplemented with glutamine as well as a difference between
rhGH in cotherapy with glutamine as compared to diet supplemented with
glutamine.

The sponsor's analysis focused on two pairwise comparisons; however, an
additional comparison may be obtained from the data. The relationship
between rhGH alone versus rhGH in cotherapy with glutamine may be
ascertained and provide some insight into the effect of glutamine. The
sponsor applied the Dunnett-Hsu test which can appropriately be used to
control the type I error rate when comparison of interest are between
treatments and a single control. In order to extend comparisons to
include all pairwise comparisons, I applied multiple t-tests (unadjusted
for multiplicity) as well as a Tukey-Kramer test (adjusted for
multiplicity). The unadjusted analysis yielded a statistically
significant result (p = 0.0226) in reduction in total volume when
comparing rhGH and the cotherapy of rhGh and glutamine. The result
suggested a glutamine effect. In contrast, a borderline statistically
significant difference (p = 0.0574) in reduction in total IPN volume was
achieved when applying an adjusted analysis to the comparison of
interest. The result suggested a negligible glutamine effect. The
primary efficacy variable in these analyses was the total IPN volume
defined as the sum of IPN volume, SLE, and hydration fluids.
Additionally, no statistically significant difference (p = 0.1911 and p
= 0.3868, unadjusted and adjusted respectively) in reduction in IPN
utilization was found to exist between rhGH and the rhGH and glutamine
cotherapy when excluding the SLE and hydration fluid components.

All aforementioned analyses and results ignore data from the specialized
oral diet. Due to the daily changes in the oral diet after randomization
and the complex relationship between the diet and total IPN volume, an
unbiased statistical analysis of total IPN volume adjusting for the
effect of diet was not possible. However, summary data on the various
components of the diet provide clinicians with a descriptive
clarification of the oral diet intake during the study. The sponsor
provided data and descriptive analyses for 5 of the 6 components of the
oral diet, namely oral fluids, oral calories, protein, carbohydrates,
and fat. An increase in intake from week 2 to week 6 was noted in all
diet components across each treatment group. Specifically, there was a
mean increase in oral fluids of 5.0 L, 4.9 L, and 4.7 L in the
glutamine, rhGH and glutamine cotherapy, and the rhGH groups
respectively. The mean change in oral calories was 566.2 kcal, 1504.0
kcal, and 1086.4 kcal in the glutamine, rhGH and glutamine cotherapy,
and the rhGH groups respectively. The cotherapy group increased the
protein consumption by 101.9 g while the rhGH alone and glutamine alone
groups increased their protein consumption by  91.0 g and 36.6 g. The
amount of carbohydrates consumed increased across groups  (3.1 g, 62.5
g, and 74.8 g for the glutamine, rhGH, and cotherapy treatments).
Lastly, an increase across groups was also noted in the amount of fat in
the oral diet (17.1 g, 49.9 g, and 68.3 g respectively). Detailed
descriptive tables of the components of the diet are in the Appendix. Of
note, the resulting values produced by my analysis of the data were
slightly varied from that of the sponsor. In that the variations were
small, an attempt to explain the differences was neglected.

The sponsor additionally submitted (21 May 2003) analytical results
pertaining to the specialized oral diet. The results were produced via
ANCOVA models with effects for treatment and baseline components of the
oral diet (separate model per component). Moreover, the change from
baseline to week 6 in diet components was examined via ANCOVA models
with effects for treatment and change in components. Since the
relationship between diet and IPN volume was complex and the oral diet
varied after randomization, the aforementioned analyses by the sponsor
were not of focus in my review.

### Statistical Reviewer's Findings

During the course of my review, some concern arose regarding the primary
efficacy variable. The primary efficacy variable as stated in NDA 21-597
was " the change in total volume of IPN from Week 2 to Week 6. Total
volume was defined as the sum of the volumes of IPN, supplemental lipid
emulsion (SLE), and intravenous hydration fluid administered each week."
Prior communications and correspondences suggested the primary endpoint
was total IPN volume excluding the SLE and hydration fluid components.
Specifically, I investigated the initial protocol submitted 31 August
1995 and the subsequent four amendments (dated 28 August 1998, 05
November 1999, 28 March 2000, and 19 October 2001, respectively). In the
initial protocol, the primary efficacy variable was " the change from
Control Period to the end of the Treatment Period in the total volume
(ml/day or L/week) of IPN required by the patient(s) for nutritional
support." In amendments 1-3, the primary efficacy variable remained
unchanged from that defined in the original protocol. The definition of
the primary efficacy variable in Amendment 4 corresponds to the
submitted NDA. My analysis suggests that IPN volume is the primary
contributor to the total IPN volume. Moreover, results regarding the two
pairwise comparisons of primary interest to the sponsor are equivalent
for the analysis of the total IPN volume including SLE and hydration
fluids and the analysis of the volume excluding the SLE and hydration
fluids. Thus, the initial concern has been diminished. However of note,
results vary when the pairwise comparison between rhGH and the cotherapy
are considered. A statistically significant difference in reduction in
IPN utilization was not found to exist between rhGH and the rhGH and
glutamine cotherapy when the SLE and hydration fluids were excluded from
the definition of total IPN volume. Results varied when the efficacy
variable was defined as the sum of three components (Section 2.3.3).

Background or historical documents indicate that the agency expressed
concern regarding the use of a single study ( and single center) to
establish the safety and efficacy of Serostim^®^ for the treatment of
short bowel syndrome. The concern is compounded by the previous
collaboration between Sereno Laboratories, Inc. and a second sponsor and
subsequent dissolution of the collaboration. Thus, a degree of
uncertainty exists regarding the dissemination of information before and
after the dissolution of the collaboration. In as much in a meeting
dated 6 September 2002, Sereno Laboratories, Inc. asked for confirmation
that the safety and efficacy analysis plan would be adequate to support
filing. As stated in the meeting minutes, " The Agency agreed that, with
the caveat that additional information would be necessary, a review of
the results could begin." I would defer such discussion regarding the
scope of additional information as it pertains to the need for
additional centers or an additional study to the review of the medical
officer, Dr. Hugo Gallo-Torres.

At the aforementioned meeting, the agency expressed concern regarding
the contribution of the specialized oral diet (SOD) to the efficacy. The
SOD was standardized with regard to the relative composition of
carbohydrates, fat, and protein; however, the diet was tailored to meet
individualized needs of the patients. The meeting minutes reflect an
agreement that states, " The firm should quantify the intake in diet to
determine whether there is an imbalance between treatment groups." The
requested quantification of diet intake was provided to the agency on 21
May 2003 and was subsequently reviewed. Results indicated an increase in
intake from week 2 to week 6 in all diet components across each
treatment group. The clinical relevance of the increases is deferred to
the medical review.

## Findings in Special/Subgroup Populations

Additional analyses examined the relationship between the primary
efficacy variable and patients' age, gender, and race, respectively. The
change in total IPN volume from baseline to week 4 was analyzed via
ANCOVA models including the subgroup variable as a covariate. The age
variable was categorized utilizing two subgroups, ages greater than or
equal to 65 and ages less than 65. The variable denoting race was
categorized utilizing two subgroups, Caucasian and non-Caucasian.
Pairwise comparisons were assessed via the Dunnett-Hsu test. Due to the
small sample sizes generated from analyses of subgroups, analyses are
considered exploratory.

Thirty-three patients were younger than 65 with the remaining 12
patients being classified as greater than or equal to 65. Among younger
patients (less than 65), the mean change in total volume from week 2 to
week 6 was 6.44 L, 8.32 L, and 4.04 L in the rhGH only, rhGH and
glutamine in cotherapy, and glutamine only groups respectively. Among
older patients, the mean change was 5.41 L, 7.29 L, and 3.01 L in the
three respective treatment groups (as presented by the sponsor). Of
note, only one older patient received glutamine only. Adjusted analysis
supported the efficacy of the rhGH and glutamine in cotherapy for the
treatment of short bowel syndrome.

Seventy-one percent of patients were female. Among females, the mean
change in total volume from week 2 to week 6 was 6.51 L, 8.24 L, and
2.85 L in the rhGH only, rhGH and glutamine in cotherapy, and glutamine
only groups respectively (as presented by the sponsor). Among males, the
mean change was 5.32 L, 7.89 L, and 6.07 L in the three respective
treatment groups with 4, 5, and 3 persons per group. Analyses adjusted
for gender supported the efficacy of the rhGH and glutamine in cotherapy
for the treatment of short bowel syndrome.

Thirty-two patients were Caucasian. Among Caucasian subjects, the mean
change in total volume from week 2 to week 6 was 6.26 L, 8.31 L, and
4.29 L in the rhGH only, rhGH and glutamine in cotherapy, and glutamine
only groups respectively. Among non-Caucasians, the mean change was 5.41
L, 7.46 L, and 3.44 L in the three respective treatment groups (as
presented by the sponsor). Analyses adjusted for race supported the
efficacy of the rhGH and glutamine in cotherapy for the treatment of
short bowel syndrome.

The sponsor did not propose any efficacy claims for any subgroup of
patients. Overall, the results were consistent and lend support to the
findings presented in the preceding section.

##  Conclusions and Recommendations

Sereno Laboratories, Incorporated has proposed Serostim^®^, a
recombinant human growth hormone (rhGH), for the improvement of residual
gut absorptive function in patients with short bowel syndrome (SBS). A
primary claim of the sponsor is that rhGH, administered singly and as
cotherapy with glutamine, reduces the total intravenous parenteral
nutrition (IPN) volume requirements of SAS patients. The evidence taken
from the reviewed study indicates statistical support favoring
Serostim^®^ for the treatment of short bowel syndrome. Additional claims
are made regarding IPN calorie content and frequency of IPN
administration. Evidence further suggests that Serostim^®^ significantly
reduces both IPN calorie content and frequency of administration among
SBS patients.

Of note, all study participants received an oral diet individualized to
meet nutritional needs. Moreover, modifications to the diet throughout
the treatment period were necessary to maintain adequate nutritional
status. Due to the daily changes to the diet after randomization and the
potentially complex relationship between diet and total IPN volume, an
unbiased statistical analysis of total IPN adjusting for the effect of
diet is not possible. However, data on the diet and nutritional status
of patients may provide clinicians with a descriptive clarification of
the nature and strength of the relationship between diet and IPN
utilization over time. Summary data suggest an increase in the
components of the oral diet from week 2 to week 6 across each treatment
group.

Furthermore, issues including the clinical significance of the rhGH
effect, the appropriateness of the endpoints, and the appropriateness of
a single study for the proposed indication are deferred to the medical
review of Dr. Hugo Gallo-Torres.

## Labelling

A portion of the sponsor's proposed label reads as follows:

> A randomized, double-blind, controlled, parallel-group multi-center
> Phase 3 clinical study evaluated the efficacy and safety of the
> administration of Serostim^®^ in subjects with Short Bowel Syndrome
> (SBS) who are dependent on intravenous parenteral nutrition (IPN) for
> nutritional support. The primary endpoint was the change in weekly
> total IPN volume. The secondary endpoints were the change in weekly
> IPN caloric content and the change in the frequency of IPN
> administration per week. Subjects received either Serostim^®^ with a
> specialized diet supplemented with glutamine (Group 1), Serostim^®^
> with a specialized diet not supplemented with glutamine (Group 2) or
> Serostim^®^ placebo with a specialized diet supplemented with
> glutamine (Group 3). The study subjects were randomized to 1 of the 3
> treatment arms in a 2:2:1 ratio. There were no significant differences
> in age, sex, race, or weight among the three treatment groups. The
> subject resection history and IPN history (frequency, volume and
> calories) were also similar across all three treatment groups. After 4
> weeks of treatment, the subjects in Group 1 and Group 2 significantly
> reduced their IPN volume requirements (p\<0.001 for Group 1 and
> p=0.042 for Group 2), their IPN calorie content (p\<0.001 for Group 1
> and p=0.005 for Group 2), and their weekly frequency of IPN
> administration (p\<0.001 for Group 1 and p=0.025 for Group 2) relative
> to the change seen in Group 3.

![](media/image3.wmf)The reviewed study was conducted at two sites;
however, one site enrolled only three patients. I would, therefore, not
recommend the use of the "multi-center" wording. In addition, I
recommend the primary efficacy variable be defined as the the sum of the
volumes of IPN, supplemental lipid emulsion (SLE), and intravenous
hydration fluid administered each week for clarity. I further recommend
a visual aid such as a table or graph for aid in interpretation. I
suggest the following : 

> \* p-values denote comparisons between Groups 1 and 2 relative to
> Group 3.

After four weeks of treatment, the subjects in Group 1 significantly
reduced their IPN volume requirements, IPN calorie content, and weekly
frequency of IPN administration relative to the change seen in Group 3.
Specifically, there existed a decrease in IPN utilization over the
treatment duration of 7.7 L, 5.9 L, and 3.8 L in the three respective
groups. Moreover, Group 2 experienced borderline significant reductions
in IPN utilization as compared to Group 3 and highly significant
reductions in IPN calorie content, and weekly frequency of IPN
administration.

Lastly, a claim is made regarding the persistence of the effect. I would
caution against such a claim, as the duration of effect was a secondary
objective with limited focus. A claim of duration or persistence would
require a more in-depth investigation and possible adjustments for
multiplicity in the analyses.

## Appendix 

Summary of Demographic and Baseline Characteristics by Treatment Group

+-------------+-------------+------------------+-------------+-------+
| **Chara     | **rhGH +    | **rhGH +         | **S         | **p   |
| cteristic** | SOD**       | SOD\[GLN\]**     | OD\[GLN\]** | -valu |
|             |             |                  |             | e\*** |
|             | **N=16**    | **N=16**         | **N=9**     |       |
|             |             |                  |             |       |
|             | **n (%)**   | **n (%)**        | **n (%)**   |       |
+-------------+-------------+------------------+-------------+-------+
| **Age       |             |                  |             |       |
| (years)**   |             |                  |             |       |
+-------------+-------------+------------------+-------------+-------+
|  Mean       | 50.5        | 52.5             | 45.0        | 0.521 |
+-------------+-------------+------------------+-------------+-------+
|  St. Dev.   | 17.1        | 14.4             | 15.5        |       |
+-------------+-------------+------------------+-------------+-------+
|  Median     | 53          | 53               | 42          |       |
+-------------+-------------+------------------+-------------+-------+
|  Min, Max   | 26, 74      | 20,73            | 24, 75      |       |
+-------------+-------------+------------------+-------------+-------+
|  \<65       | 12 (75)     | 13 (81)          | 8 (89)      |       |
+-------------+-------------+------------------+-------------+-------+
|  65         | 4 (25)      | 3 (19)           | 1 (11)      |       |
+-------------+-------------+------------------+-------------+-------+
| **Sex**     |             |                  |             | 0.913 |
+-------------+-------------+------------------+-------------+-------+
|  Male       | 4 (25)      | 5 (31)           | 3 (33)      |       |
+-------------+-------------+------------------+-------------+-------+
|  Female     | 12 (75)     | 11 (69)          | 6 (67)      |       |
+-------------+-------------+------------------+-------------+-------+
| **Race**    |             |                  |             | 0.064 |
+-------------+-------------+------------------+-------------+-------+
|  Caucasian  | 15 (94)     | 12 (75)          | 5 (56)      |       |
+-------------+-------------+------------------+-------------+-------+
|  No         | 1 (6)       | 4 (25)           | 4 (44)      |       |
| n-Caucasian |             |                  |             |       |
+-------------+-------------+------------------+-------------+-------+
| **W         |             |                  |             | 0.977 |
| eight(kg)** |             |                  |             |       |
| †           |             |                  |             |       |
+-------------+-------------+------------------+-------------+-------+
|  Mean       | 61.4        | 62.1             | 61.3        |       |
+-------------+-------------+------------------+-------------+-------+
|  St. Dev.   | 10.4        | 11.4             | 8.5         |       |
+-------------+-------------+------------------+-------------+-------+
| **Number of |             |                  |             |       |
| yrs since   |             |                  |             |       |
| resection** |             |                  |             |       |
+-------------+-------------+------------------+-------------+-------+
|  Mean       | 5.1         | 4.6              | 3.9         | 0.855 |
+-------------+-------------+------------------+-------------+-------+
|  St. Dev.   | 5.9         | 4.6              | 3.9         |       |
+-------------+-------------+------------------+-------------+-------+
| **Length of |             |                  |             |       |
| residual    |             |                  |             |       |
| jeju        |             |                  |             |       |
| num-ileum** |             |                  |             |       |
+-------------+-------------+------------------+-------------+-------+
|  Mean       | 84.2        | 68.4             | 62.3        | 0.584 |
+-------------+-------------+------------------+-------------+-------+
|  St. Dev.   | 49.8        | 32.7             | 30.8        |       |
+-------------+-------------+------------------+-------------+-------+
| **Colon     |             |                  |             |       |
| Intact**    |             |                  |             |       |
+-------------+-------------+------------------+-------------+-------+
|  Percent    | 67.1        | 52.6             | 61.8        | 0.442 |
+-------------+-------------+------------------+-------------+-------+
|  St. Dev.   | 28.1        | 33.5             | 36.3        |       |
+-------------+-------------+------------------+-------------+-------+
| **Number of |             |                  |             |       |
| days per    |             |                  |             |       |
| week of IPN |             |                  |             |       |
| admin       |             |                  |             |       |
| istration** |             |                  |             |       |
+-------------+-------------+------------------+-------------+-------+
|  Mean       | 5.2         | 5.5              | 5.9         | 0.680 |
+-------------+-------------+------------------+-------------+-------+
|  St. Dev.   | 1.9         | 1.9              | 1.5         |       |
+-------------+-------------+------------------+-------------+-------+
| **IPN       |             |                  |             |       |
| Volume per  |             |                  |             |       |
| week        |             |                  |             |       |
| (mL/wk)**   |             |                  |             |       |
+-------------+-------------+------------------+-------------+-------+
|  Mean       | 13.8        | 13.0             | 13.1        | 0.880 |
+-------------+-------------+------------------+-------------+-------+
|  St. Dev.   | 5.3         | 4.3              | 4.6         |       |
+-------------+-------------+------------------+-------------+-------+
| **IPN       |             |                  |             |       |
| calories    |             |                  |             |       |
| per week    |             |                  |             |       |
| (kcal/wk)** |             |                  |             |       |
+-------------+-------------+------------------+-------------+-------+
|  Mean       | 11620.8     | 10403.8          | 10224.9     | 0.814 |
+-------------+-------------+------------------+-------------+-------+
|  St. Dev.   | 4167.3      | 2496.3           | 4037.9      |       |
+-------------+-------------+------------------+-------------+-------+

\* Categorical variables were compared by using Fisher's exact test.
Continuous variables were compared by using ANOVA with main effect term
of treatment. Treatment differences were compared via a Kruskal-Wallis
test for length of residual jejunum-ileum.

† Weight is the average of each patient's weight at 1 month and 2 months
before screening.

**Descriptive Statistics for Components of the Oral Diet**

+-------------+-------------+-------------+-------------+-------------+
|             |             | **GLN**     | **rhGH**    | **rhGH +    |
|             |             |             |             | GLN**       |
|             |             | **(n=9)**   | **(n=15)**  |             |
|             |             |             |             | **(n=16)**  |
+-------------+-------------+-------------+-------------+-------------+
| **[Oral     |             |             |             |             |
| Fluid       |             |             |             |             |
| (           |             |             |             |             |
| L/week)]{.u |             |             |             |             |
| nderline}** |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Week 2      | Mean        | 15.1(5.8)   | 16.5(5.6)   | 15.5 (4.0)  |
+-------------+-------------+-------------+-------------+-------------+
|             | Median      | 14.1        | 15.7        | 14.6        |
+-------------+-------------+-------------+-------------+-------------+
|             | Range       | (5.3, 24.2) | (6.5, 29.5) | (7.8, 23.5) |
+-------------+-------------+-------------+-------------+-------------+
|             |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Week 6      | Mean        | 20.1(8.9)   | 21.3(4.2)   | 20.4(2.5)   |
+-------------+-------------+-------------+-------------+-------------+
|             | Median      | 19.4        | 20.3        | 19.7        |
+-------------+-------------+-------------+-------------+-------------+
|             | Range       | (8.6, 40.3) | (14.6,      | (15.4,25.1) |
|             |             |             | 32.1)       |             |
+-------------+-------------+-------------+-------------+-------------+
|             |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Change      | Mean        | 5.0(6.5)    | 4.7(3.7)    | 4.9(3.7)    |
+-------------+-------------+-------------+-------------+-------------+
|             | Median      | 3.9         | 5.1         | 4.5         |
+-------------+-------------+-------------+-------------+-------------+
|             | Range       | (-4.3,20.0) | (-2.6,12.9) | (-2.4,11.2) |
+-------------+-------------+-------------+-------------+-------------+
| **[Oral     |             |             |             |             |
| Calories    |             |             |             |             |
| (kca        |             |             |             |             |
| l/Week)]{.u |             |             |             |             |
| nderline}** |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Week 2      | Mean        | 15          | 1596        | 1542        |
|             |             | 791.2(5270) | 6.5(4935.3) | 0.1(2875.6) |
+-------------+-------------+-------------+-------------+-------------+
|             | Median      | 17199.0     | 16212.0     | 14752.0     |
+-------------+-------------+-------------+-------------+-------------+
|             | Range       | (8442.0,    | (5635       | (9926       |
|             |             | 2358.3)     | .0,22743.0) | .0,21168.0) |
+-------------+-------------+-------------+-------------+-------------+
|             |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Week 6      | Mean        | 1635        | 1705        | 1692        |
|             |             | 7.4(4632.5) | 2.9(3395.0) | 4.0(3615.9) |
+-------------+-------------+-------------+-------------+-------------+
|             | Median      | 15183.0     | 16800.0     | 16761       |
+-------------+-------------+-------------+-------------+-------------+
|             | Range       | (8911       | (10192      | (11466      |
|             |             | .0,25228.0) | .0,22729.0) | .0,23114.0) |
+-------------+-------------+-------------+-------------+-------------+
|             |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Change      | Mean        | 56          | 108         | 150         |
|             |             | 6.2(3548.2) | 6.4(4013.1) | 4.6(1963.1) |
+-------------+-------------+-------------+-------------+-------------+
|             | Median      | 763.0       | 308.0       | 1386.0      |
+-------------+-------------+-------------+-------------+-------------+
|             | Range       | (-452       | (-642       | (-283       |
|             |             | 2.0,6741.0) | 6.0,9814.0) | 5.0,4361.0) |
+-------------+-------------+-------------+-------------+-------------+
| **[Protei   |             |             |             |             |
| n(g/wk)]{.u |             |             |             |             |
| nderline}** |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Week 2      | Mean        | 8           | 8           | 8           |
|             |             | 99.1(319.6) | 26.5(274.9) | 17.3(137.5) |
+-------------+-------------+-------------+-------------+-------------+
|             | Median      | 854.0       | 882.0       | 798.0       |
+-------------+-------------+-------------+-------------+-------------+
|             | Range       | (46         | (28         | (57         |
|             |             | 9.0,1484.0) | 7.0,1232.0) | 4.0,1204.0) |
+-------------+-------------+-------------+-------------+-------------+
|             |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Week 6      | Mean        | 9           | 9           | 9           |
|             |             | 35.7(235.6) | 17.5(195.6) | 19.2(185.7) |
+-------------+-------------+-------------+-------------+-------------+
|             | Median      | 861.0       | 924.0       | 924.0       |
+-------------+-------------+-------------+-------------+-------------+
|             | Range       | (56         | (518.0,     | (61         |
|             |             | 7.0,1379.0) | 1246.0)     | 6.0,1302.0) |
+-------------+-------------+-------------+-------------+-------------+
|             |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Change      | Mean        | 36.6(208.1) | 91.0        | 1           |
|             |             |             | (176.7)     | 01.9(140.3) |
+-------------+-------------+-------------+-------------+-------------+
|             | Median      | 21.0        | 105.0       | 101.5       |
+-------------+-------------+-------------+-------------+-------------+
|             | Range       | (-2         | (-1         | (-189.0,    |
|             |             | 59.0,378.0) | 75.0,490.0) | 336.0)      |
+-------------+-------------+-------------+-------------+-------------+
| **[C        |             |             |             |             |
| arbohydrate |             |             |             |             |
| s(g/wk)]{.u |             |             |             |             |
| nderline}** |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Week 2      | Mean        | 18          | 19          | 19          |
|             |             | 10.7(640.7) | 68.4(560.4) | 11.9(477.4) |
+-------------+-------------+-------------+-------------+-------------+
|             | Median      | 2107.0      | 1960.0      | 1781.5      |
+-------------+-------------+-------------+-------------+-------------+
|             | Range       | (79         | (77         | (123        |
|             |             | 1.0,2604.0) | 0.0,2849.0) | 9.0,3038.0) |
+-------------+-------------+-------------+-------------+-------------+
|             |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Week 6      | Mean        | 18          | 20          | 19          |
|             |             | 13.8(604.0) | 30.9(489.4) | 86.7(497.5) |
+-------------+-------------+-------------+-------------+-------------+
|             | Median      | 1694.0      | 1981.0      | 1911.0      |
+-------------+-------------+-------------+-------------+-------------+
|             | Range       | (84         | (112        | (130        |
|             |             | 7.0,2989.0) | 7.0,2828.0) | 2.0,3283.0) |
+-------------+-------------+-------------+-------------+-------------+
|             |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Change      | Mean        | 3.11(549.0) | 62.5(541.3) | 74.8(226.5) |
+-------------+-------------+-------------+-------------+-------------+
|             | Median      | -28.0       | 21.0        | 101.5       |
+-------------+-------------+-------------+-------------+-------------+
|             | Range       | (-665.0,    | (-847.0,    | (-2         |
|             |             | 714.0)      | 1190.0)     | 80.0,602.0) |
+-------------+-------------+-------------+-------------+-------------+

+-------------+-------------+-------------+-------------+-------------+
|             |             | **GLN**     | **rhGH**    | **rhGH +    |
|             |             |             |             | GLN**       |
|             |             | **(n=9)**   | **(n=15)**  |             |
|             |             |             |             | **(n=16)**  |
+-------------+-------------+-------------+-------------+-------------+
| **[Fa       |             |             |             |             |
| t(g/wk)]{.u |             |             |             |             |
| nderline}** |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Week 2      | Mean        | 5           | 5           | 4           |
|             |             | 50.7(195.2) | 31.5(199.3) | 97.9(125.9) |
+-------------+-------------+-------------+-------------+-------------+
|             | Median      | 567.0       | 525.0       | 514.5       |
+-------------+-------------+-------------+-------------+-------------+
|             | Range       | (3          | (1          | (2          |
|             |             | 15.0,931.0) | 54.0,791.0) | 94.0,749.0) |
+-------------+-------------+-------------+-------------+-------------+
|             |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Week 6      | Mean        | 5           | 5           | 5           |
|             |             | 67.8(154.5) | 81.5(133.6) | 66.1(158.5) |
+-------------+-------------+-------------+-------------+-------------+
|             | Median      | 581.0       | 574.0       | 535.5       |
+-------------+-------------+-------------+-------------+-------------+
|             | Range       | (3          | (3          | (3          |
|             |             | 15.0,861.0) | 50.0,756.0) | 36.0,903.0) |
+-------------+-------------+-------------+-------------+-------------+
|             |             |             |             |             |
+-------------+-------------+-------------+-------------+-------------+
| Change      | Mean        | 17.1(137.8) | 50.0(145.9) | 68.3(108.3) |
+-------------+-------------+-------------+-------------+-------------+
|             | Median      | 49.0        | 35.0        | 80.5        |
+-------------+-------------+-------------+-------------+-------------+
|             | Range       | (-2         | (-2         | (-1         |
|             |             | 03.0,266.0) | 73.0,315.0) | 19.0,252.0) |
+-------------+-------------+-------------+-------------+-------------+

**STUDY DIET (as presented by the sponsor)**

The diet employed for SBS patients consists entirely of foods that
patients can purchase from local sources. The diet provides
approximately 50% to 55% of total daily calories from carbohydrates, 20%
from protein, and 25% to 30% from fat. Rehydration fluids and dietary
supplements (e.g., multivitamins, minerals, calcium, and zinc) are also
provided. The objective of the diet is to ensure that each patient is
able to maintain, through oral feeding, adequate nutritional status that
can promote nutrient absorption and independence from IPN following
discharge from the clinic.

The diet varies among patients according to their individual
requirements. In general, the diet used in conjunction with the rhGH
treatment of SBS patients includes the following:

1.  **Calories**

The daily caloric requirements are determined by multiplying the
following variables:

resting energy expenditure (REE), calculated from standard equations or
indirect

calorimetry; an activity factor (AF), based on the patient\'s level of
physical activity;

and a malabsorption factor (MF), based on the patient\'s degree of
malabsorption and

diarrhea.

Daily Calories: REE x AF (1.2 to 1.5) x MF (1.2 to 1.7).

Nutrient-dense foods are provided to maximize caloric intake and limit
food volume.

Serving of food to the patients is distributed throughout the day (6 to
8 meals

per day).

2.**0 Carbohydrates**

Carbohydrates are provided to equal 50% to 55% of total daily caloric
intake.

Complex carbohydrates are emphasized (e.g., rice, potato, pasta, cereal
and

grain products).

Intake of simple sugars is limited (e.g., lactose, sucrose, and
fructose).

3.0 **Proteins**

Protein is provided to equal 20% of total daily caloric intake.

A significant source of protein is provided at each meal (6 to 8 times
per day).

Protein sources rich in essential amino acids (chicken, fish, and
turkey) are

emphasized.

4.0 **Fat**

Fat is provided to equal 25% to 30% percent of total caloric intake.

Fats (oils and margarine) rich in linolenic and linoleic acid (soybean
oil and

safflower oil) are provided to prevent essential fatty-acid deficiency.

5.0 **Fluids**

Oral rehydration solutions (carbohydrate and sodium-containing
beverages)

are provided as the primary source of hydration. Oral rehydration
solutions

are initiated at 1.5 liters per day and are increased as needed, based
on stool

volumes and urine output.

Intake of hypo-osmolar and hyperosmolar beverages such as water, regular

soda, and most fruit juices is limited.

Fluid intake is distributed throughout the day.

6.0 **Specific Oral Nutrients**

Specific oral nutrients are included, or excluded, to maintain
appropriate serum

electrolyte concentrations, prevent nutrient deficiencies, and avoid the
long-term

complications associated with altered bowel function.

**Included Components** (commercially available in grocery, drug, and

health-food stores).

-   Multivitamin/mineral supplements (1 to 2 tablets every day)

--- Vitamin B12 (100 to 300 JLg every month -given intramuscularly if

the terminal ileum is missing)

--- Fat-soluble vitamins (A, E, D, K) (These vitamins may be provided

if indicated in increased doses to treat or prevent deficiencies. )

-   Calcium (1500 to 3000 mg daily)

--- Zinc (15 mg daily if stool volumes are greater than 1 Ud)

--- Other electrolytes (including potassium, magnesium, and phosphorus)

as required to maintain serum concentrations

##### Excluded Components {#excluded-components .unnumbered}

Oxalate (Food and beverages rich in oxalate are restricted to decrease
the

likelihood of calcium-oxalate renal stone formation).

7.0 **Diet Individualization**

The diet is tailored to meet the individual nutritional needs of each
patient. Upon admission to the in-patient facility, each patient\'s
nutritional and hydration status is assessed. In addition, all patients
undergo extensive diet education, both in the classroom setting and via
individualized counseling sessions. The patient\'s oral intake is
assessed for adequacy and compliance to the prescribed diet. Food
sensitivities are identified by reviewing the recorded intake and the
volume of stool output over a given time period within a given day. The
diet is then adjusted to eliminate or restrict a nutrient (e.g.,
lactose) that appears to be contributing to increased stool output.
Specific supplements are added to correct nutrient deficiencies
identified during the Baseline assessment and during serum evaluations.

**IPN WEANING (as presented by the sponsor)**

IPN requirements will be reduced when the patient demonstrates all 3 of
the following:

1.  Ability to hydrate, demonstrated by the following:

• A positive enteral balance (defined as enteral fluid intake \[mL\]
minus volume of stool output \[mL\]) greater than or equal to
approximately 500 cc per day or the patient\'s calculated insensible
fluid losses greater than or equal to approximately 12 mUkg/d, and/or

• A urine volume, demonstrated by the following:

--- Greater than or equal to 0.5 cc/kg for 24 hours on the nights that
the patient does not infuse IPN, or

--- Approximately 75% of the patient\'s calculated minimum urine volume
prior to nighttime infusion

2.0 Ability to maintain serum electrolytes within the limits of normal
range with or

without the use of enteral electrolyte supplement(s)

3.0 Ability to sustain an appropriate body weight demonstrated by the
following:

• An ability to maintain body weight while maintaining total body water
(reflected by a relatively stable measurement of whole body resistance
as measured by bioelectrical impedance analysis), or an ability to gain
body weight while maintaining total body water (reflected by a
relatively stable or decreasing measurement of whole body resistance
measured by bioelectrical impedance analysis), and/or

• An ability to consistently consume 80% to 100% of estimated total
caloric requirements (as calculated from standard equations)

[^1]: Byrne TA, Nompleggi DJ, Wilmore DW. Advances in the management of
    patients with intestinal failure. Transplant Proc 1996;
    28(5):2683-2690.