# Medical Officer Review of NDA 21-597:

# Serostim^®^ \[somatropin (rDNA origin) for injection\]

# 

# Treatment of Short Bowel Syndrome

**Date Submitted**: 31 October, 2002

**Date Completed**: 22 May, 2003

**Applicant:** Serono, Inc.

One Technology Place

Rockland, MA 02370

Contact person: Pamela Williamson Joyce

Vice President, Regulatory Affairs

**Drug:** **Proprietary Name :** Serostim^®^

**Non-proprietary name:** somatropin (rDNA origin) for injection

**Chemical Name:** human Growth Hormone (hGH)

A single polypeptide chain of 191 amino acids

having the normal structure of the principal

growth stimulating hormone obtained from the

anterior lobe of the human pituitary gland.

(1) Growth Hormone (human);

> \(2\) somatotropin (human)

**Molecular formula:** C~990~H~1528~N~262~O~300~S~7~

**Molecular weight:** 22,124

**Formulation:** lyophilized

**Route of Administration:** subcutaneous

**Strengths:** 4mg, 5mg, 6mg, 8.8mg

**Related NDA**: 20-604

**Reviewer**: Hugo E. Gallo-Torres, MD, PhD, PNS

Medical Team Leader (GI Drugs)

HFD-180

# Table of Contents

Table of Contents [2](#table-of-contents)

Executive Summary [5](#executive-summary)

I. Recommendations [5](#i.-recommendations)

A. Recommendation on Approvability
[5](#a.-recommendation-on-approvability)

B. Recommendation on Phase 4 Studies and/or Risk Management Steps
[6](#__RefHeading___Toc514120870)

II\. Summary of Clinical Findings [6](#ii.-summary-of-clinical-findings)

A. Brief Overview of Clinical Program
[6](#a.-brief-overview-of-clinical-program)

B. Efficacy [6](#b.-efficacy)

C. Safety [7](#c.-safety)

D. Dosing [7](#d.-dosing)

E. Special Populations [8](#special-populations)

Clinical Review [9](#clinical-review)

I. Introduction and Background [9](#i.-introduction-and-background)

A. Drug Established and Proposed Trade Name, Drug Class, Sponsor's
Proposed Indication(s), Dose, Regimens, Age Groups
[9](#a.-drug-established-and-proposed-trade-name-drug-class-sponsors-proposed-indications-dose-regimens-age-groups)

B. State of Armamentarium for Indication(s)
[10](#b.-state-of-armamentarium-for-indications)

C. Important Milestones in Product Development
[12](#important-milestones-in-product-development)

D. Other Relevant Information [14](#d.-other-relevant-information)

E. Important Issues with Pharmacologically Related Agents
[14](#e.-important-issues-with-pharmacologically-related-agents)

II\. Clinically Relevant Findings From Chemistry, Animal Pharmacology
and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other
Consultant Reviews
[16](#ii.-clinically-relevant-findings-from-chemistry-animal-pharmacology-and-toxicology-microbiology-biopharmaceutics-statistics-andor-other-consultant-reviews)

III\. Human Pharmacokinetics and Pharmacodynamics
[18](#iii.-human-pharmacokinetics-and-pharmacodynamics)

IV\. Description of Clinical Data and Sources
[19](#iv.-description-of-clinical-data-and-sources)

A. Overall Data [19](#a.-overall-data)

B. Tables Listing the Clinical Trials
[19](#b.-tables-listing-the-clinical-trials)

C. Postmarketing Experience [19](#c.-post-marketing-experience)

D. Literature Review [20](#d.-literature-review)

V. Clinical Review Methods [21](#v.-clinical-review-methods)

A. How the Review was Conducted [21](#a.-how-the-review-was-conducted)

B. Overview of Materials Consulted in Review
[22](#b.-overview-of-materials-consulted-in-review)

D. Were Trials Conducted in Accordance with Accepted Ethical Standards
[31](#__RefHeading___Toc514120897)

E. Evaluation of Financial Disclosure
[31](#e.-evaluation-of-financial-disclosure)

VI\. Integrated Review of Efficacy
[31](#vi.-integrated-review-of-efficacy)

A. Brief Statement of Conclusions
[31](#a.-brief-statement-of-conclusions)

B. General Approach to Review of the Efficacy of the Drug
[31](#b.-general-approach-to-review-of-the-efficacy-of-the-drug)

C. Detailed Review of Trials by Indication
[32](#detailed-review-of-trials-by-indication)

D. Efficacy Conclusions [47](#d.-efficacy-conclusions)

VII\. Integrated Review of Safety
[47](#vii.-integrated-review-of-safety)

A. Brief Statement of Conclusions
[47](#a.-brief-statement-of-conclusions-1)

B. Description of Patient Exposure
[47](#b.-description-of-patient-exposure)

C. Methods and Specific Findings of Safety Review
[48](#c.-methods-and-specific-findings-of-safety-review)

D. Adequacy of Safety Testing [48](#d.-adequacy-of-safety-testing)

VIII\. Dosing, Regimen, and Administration Issues
[49](#viii.-dosing-regimen-and-administration-issues)

IX\. Use in Special Populations [50](#ix.-use-in-special-populations)

X. Other 47

XI\. Conclusions and Recommendations
[52](#xi.-conclusions-and-recommendations)

A. Conclusions [52](#a.-conclusions)

B. Recommendations [52](#b.-recommendations)

**Clinical Review for NDA 21-597**

# Executive Summary

## I. Recommendations

### A. Recommendation on Approvability

> Serostim^®^ \[somatropin (rDNA origin)\], a form of human growth
> hormone produced by recombinant DNA technology, is already marketed
> for the **treatment of AIDS wasting or cachexia.**
>
> The sponsor is seeking approval of the product for a new indication,
> **treatment of Short Bowel Syndrome in patients receiving specialized
> nutritional support.** It is to be noted that the newly proposed
> indication includes the following wording: Serostim^®^ therapy should
> be used in conjunction with optimal management of Short Bowel
> Syndrome.
>
> Based on review of the efficacy and safety of this submission (NDA
> 21-597), the recommendation is that the NDA should not be approved at
> this time
>
> Several issues need to be addressed, clarified, and eventually
> resolved before the application is approved. Included among these
> issues are: 1. *Replicability* \[results of only one trial of 41
> patients (IMP20317) were submitted as part of NDA 21-597\]; 2.
> *Generalizability* \[in the final analysis, the bulk of the patients
> in Study IMP20317 originated from one center only, and, due to known
> variations in the standard of care, this center may or may not be
> representative of the general population\]; 3. The *clinical
> validity/relevance/importance* of the protocol-stipulated primary
> endpoint of efficacy \[a reduction in the Total intravenous parenteral
> nutrition (IPN) volume requirements (L/wk)\], instead of the very
> meaningful proportion of patients that, as a result of the proposed
> intervention \[administration of recombinant human growth hormone
> (rh-GH) in co-therapy with glutamine (GLN) in patients who are
> receiving a specialized oral diet (SOD)\] are **weaned off IPN** and
> **remain off IPN long-term** ; and 4. *Further exploration of*
> *dosing* .On the one hand, in Study No.7 (Table 2), the combination
> \"high-dose\" rh-GH (0.14 mg/kg/d) and glutamine did not increase body
> weight, lean body mass, fat mass and bone mass significantly compared
> to placebo treatment. On the other, in placebo-controlled, crossover
> Study No. 9 (Table 2), treatment with \"low-dose\" rh-GH (0.05
> mg/kg/d) increased intestinal absorption of energy, nitrogen and fat.
> In the latter study, body weight, lean body mass, D-xylose absorption,
> insulin-like growth factor 1 and insulin-like growth factor binding
> protein 3 increased.

#### B. Additional Recommendations

> 1\. A randomized clinical trial to determine the proportion of Short
> Bowel Syndrome patients in whom administration of recombinant human GH
> in co-therapy with glutamine, in patients who are receiving a
> specialized oral diet (rh-GH + SOD\[GLN\]) at the recommended dosage
> results .
>
> []{#__RefHeading___Toc514120870 .anchor}in the patients being weaned
> completely from IPN and remain off at least one year following
> admission into an in-home program.
>
> 2\. A study, similar in design and execution to that in Ref. 9 (Table
> 2 of the current review) to assess the efficacy and safety of low-dose
> rh-GH (0.05 mg/kg/d) when administered in co-therapy with glutamine
> and SOD in adult home parenteral nutrition-dependent Short Bowel
> Syndrome Patients.

## II. Summary of Clinical Findings 

### A. Brief Overview of Clinical Program

> The Clinical Program consists primarily of a clinical and statistical
> Study Report from Protocol IMP20317, a 3-arm, 41 patient total,
> double-blind, randomized

Clinical trial. This study was set to assess the effect of rh-GH
administered in co-therapy with glutamine and a specialized oral diet,
in the improvement of residual gut absorptive function in patients with
short bowel syndrome. Although the trial was designed to be
\"multicenter\" there were only 2 sites and one site randomized 3
patients only (1 per treatment arm) while the other randomized a total
of 38, in a 2:2:1 ratio. Consequently, **in the final analysis, this was
a single-center study**

### B. Efficacy

> There were 3 arms, identified as A, B, and C, in the trial. Group A
> consisted of active rh-GH plus glutamine placebo in patients who are
> receiving SOD.
>
> The most important comparison is that of Group B, consisting of rh-GH
> in co-therapy with (active) glutamine and a specialized oral diet, to
> Group C, a control arm, consisting of (active) glutamine plus the
> specialized oral diet plus rh-GH placebo. The protocol stipulated
> primary efficacy endpoint was the mean change **(decrease)** in Total
> IPN volume (measured in liters per week) from Week 2 to Week 6.
>
> In analyses of the Intent-to-Treat Study Population (Table 6 of the
> current review), a significant reduction in the Total IPN volume
> requirement was noted in patients who received rhGH + SOD\[GLN\] when
> compared to those receiving SOD + \[GLN\] plus rhGH placebo. The
> therapeutic gain was **3.9 liters** **less** per week. Results of this
> comparison are also supported and confirmed in the statistical
> analyses of the Evaluable for Efficacy Study Population**.**
>
> Owing to the fact that **no clinical nutrition parameters of
> efficacy** were made use of in this trial, there remain questions
> regarding the most adequate clinical tool (approach) to demonstrate
> clinically meaningful benefit of the drug in the treatment of Short
> Bowel Syndrome in patients who are dependent on IPN. There is
> uncertainty if a reduction of Total IPN volume requirement of 3.9 L/wk
> is clinically meaningful. An unquestionably meaningful and convincing
> clinical endpoint is the proportion of patients that, as a result of
> the intervention (administration of rh-GH in co-therapy with GLN in
> patients receiving SOD) are **weaned completely from IPN and remain
> off for at least 1 year** following admission into an in-home program.
> Results using this parameter (Table 8 of the current review) should be
> considered hypothesis-generating only. Results of evaluations using
> the protocol pre-stipulated study endpoints seem too incomplete to
> determine if they are predictive of clinical benefit.
>
> **NOTE:** Issues regarding the one study approach are discussed in the
> following FDA document: **Guidance for Industry. Providing Clinical
> Evidence of Effectiveness for Human Drug and Biological Products, U.S.
> Department of HHS, FDA, CDER, CBER, May 1998, Clinical 6** \[Internet
> at http://www.fda.gov/cder/guidance/index.htm\]

### C. Safety

> All in all, there are no overt safety concerns with the use of rhGH in
> co-therapy with glutamine and a specialized diet in patients with SBS
> treated for up to 16 weeks. The safety profile of the triple
> co-therapy appears to be similar to the safety profile of rhGH + SOD.
>
> No labeling revisions to include adverse events emerging from the
> IMP20317 SBS trial are proposed or needed. This is because, as
> expected, the majority of AEs reported in this study were related to
> the underlying clinical situation (SBS patients who are on Total IPN).
>
> For completeness of information purposes, the reviewer has included a
> short account of some recently published information from patients
> that were given GH for long periods of time.

### D. Dosing

> In the proposed package insert, in the DOSAGE AND ADMINISTRATION
> section, the sponsor proposes to include the following wording: \"In
> patients with Short Bowel Syndrome (SBS), Serostim^®^ should be
> administered at a dose of
>
> 0.1 mg/kg subcutaneously daily to a maximum of 8 mg daily\". Although
> the proposed revision is based on results of Clinical Trial IMP20317,
> the reviewer does not believe that the dose has been adequately
> assessed. Although different methodology may have been used, in a
> recently published well-designed clinical trial (Study No. 7 in Table
> 2 of the current review), the combination \"high-dose\" GH **(0.14
> mg/kg/d)** and glutamine did not increase body weight, lean body mass,
> fat mass, and bone mass significantly compared to placebo treatment.
> An even more recently well-designed and apparently well-executed
> published study (Study No. 9 in Table 2 of the current review) showed
> that treatment with GH at the **\"low-dose of 0.05 mg/kg/d\"**
> increased intestinal absorption of energy, nitrogen and fat. Other
> parameters that increased included body weight, lean body mass,
> D-xylose absorption, insulin-like growth factor 1 and insulin-like
> growth factor binding protein 3. It was also reported that uptake of
> GH binding protein decreased without any apparent major adverse event.
>
> A low-dose rh-GH should be considered.

### Special Populations

> Because the total number of patients who had SBS and were randomized
> to the rhGH + SOD \[GLN\] arm was so small (n= 16), evaluation of the
> use of the drug in Special Populations is not very helpful. The
> already approved Package Insert, PHARMACOKINETICS Section, includes
> information on Pediatric Patients, Gender, those with Renal
> Insufficiency, and those with Hepatic Insufficiency; but data for race
> are not available. In the PRECAUTIONS Section, information on
> Pregnancy, Nursing Women, Pediatric Use and Geriatric Use is included.

# Clinical Review 

## I. Introduction and Background

### A. Drug Established and Proposed Trade Name, Drug Class, Sponsor's Proposed Indication(s), Dose, Regimens, Age Groups

> Serostim^®^ \[somatropin (rDNA origin) for injection\] is a human
> growth hormone produced by recombinant DNA technology. Its amino acid
> sequence and structure are identical to the dominant form of human
> pituitary growth hormone.[^1]
>
> Somatropin (somatotropin) belongs to the class of growth hormones
> (GH). Somatotropin is a species-specific anabolic protein that
> promotes somatic growth, stimulates protein synthesis, and regulates
> carbohydrate and lipid metabolism. Somatotropin is secreted by the
> anterior pituitary under the regulation of the hypothalamic hormones,
> somatoliberin and somatostatin; it also increases serum levels of
> somatomedins. GHs from various species differ in amino acid sequence,
> antigenicity, isoelectric point, and in the range of animals in which
> they can produce biological responses.[^2]
>
> The sponsor\'s Serostim^®^ \[somatropin (rDNA origin)\] is approved
> for the **treatment of AIDS wasting and cachexia**, an indication
> based on analysis of surrogate endpoints in studies of up to 12 weeks
> in duration.[^3]
>
> **NOTE:** The sponsor also manufactures another form of growth
> hormone. The brand name for this form is SAIZEN^®^ \[somatropin (rDNA
> origin) for injection\], for subcutaneous or intramuscular injection.
> SAIZEN^®^ is indicated for the long-term treatment of children with
> growth failure due to inadequate secretion of endogenous growth
> hormone.
>
> Sponsor\'s proposed indication:
>
> *\"Serostim^®^ \[somatropin (rDNA origin) for injection\] is also
> indicated for the treatment of Short Bowel Syndrome in patients
> receiving specialized nutritional support. Serostim^®^ therapy should
> be used in conjunction with optimal management of Short Bowel
> Syndrome.\"*
>
> **Dose, Regimen** \[from proposed draft package insert\]: \"In
> patients with Short Bowel Syndrome (SBS), Serostim^®^ should be
> administered at a dose of 0.1 mg/kg subcutaneously daily to a maximum
> of 8 mg daily.\"
>
> **Age Groups**: The proposed draft package insert does not mention the
> age of the target population for which the new indication is proposed,
> not even in the description of the clinical trial submitted in support
> of the indication being sought.
>
> However, in the already approved package insert (for the indication
> AIDS WASTING), mention is made of Pediatric use[^4] and Geriatric
> use[^5].
>
> **NOTE:** The SBS patient population enrolled in the sponsor\'s
> clinical trial were between the ages of 20 and 75 years. Therefore,
> the SBS indication would only be supported in adults. The Agency
> cannot extrapolate findings to a pediatric population of SBS because
> there are no PK data in either adults or children with SBS. Although
> available evidence suggests that rh-GH clearances are similar in
> adults and children, no clinical studies were conducted in children
> with SBS.

### 

### B. State of Armamentarium for Indication(s) 

> There are no drugs approved for the treatment of SBS.
>
> **NOTE:** As mentioned in the recent AGA Technical Review on SBS and
> Intestinal Transplantation \[Gastroenterology 124: 1111-1134 (2003)\]
> it is unclear how many individuals in the USA suffer from SBS. But
> based in the numbers in Europe, the incidence may be ca. 2 to 4 per
> million, if one considers the incidence of home TPN \[SBS constituted
> the largest single group of patients who required home TPN (35%)\].
> With a few exceptions, in the literature, the number of patients per
> center of study (Table 2 of the current review) **varied between 8 and
> 14.** By these standards, 41 patients in sponsor\'s study IMP20317 is
> considered a relatively big trial.
>
> Pharmacologic and other non-specific management considerations are
> briefly summarized below. Two additional approaches to treatment are
> surgical procedures and intestinal transplantation but these
> approaches are beyond the scope of the present NDA review.
>
> Because of the extensive length of the small intestine and its ability
> to compensate and functionally adapt after loss of a significant
> amount of surface area, patients generally demonstrate few symptoms
> after resection of up to 50% of the small bowel. However, more
> extensive reduction of this absorptive surface is associated with
> symptoms that can often be disabling, socially incapacitating, or even
> life-threatening. SBS occurs when there is \<200 cm of bowel
> remaining.[^6] Those patients at greatest nutritional risk generally
> have a duodenostomy or a jejunoileal anastomosis with \<35 cm of
> residual small intestine, jejunocolic or ileocolic anastomosis with \<
> 60 cm of residual small intestine, or an end jejunostomy with \<115 cm
> of residual small intestine.[^7]
>
> Loss of intestinal function can be complete or partial. ***Intestinal
> Failure* is** defined as **\"**reduced gastrointestinal absorption to
> the extent that macronutrients and/or fluid supplements are
> required\", a concept that includes the need for enteral or parenteral
> supplements to maintain a normal nutritional state.[^8] Intestinal
> failure may be described as acute (usually reversible) and chronic
> (when long-term treatment over weeks, months, or longer is required,
> especially if continued treatment is needed at home). Patients who are
> unable to increase their oral intake sufficiently or are unable to
> absorb sufficient energy despite significantly increased intake, are
> defined as patients with intestinal failure and require parenteral
> nutrition support. A **standardized diet** may be useful for
> clinically defining functional SBS. For example, one recommendation is
> to maintain patients with SBS with residual colon on a
> **high-carbohydrate, low-fat diet.**[^9] But in reality there are
> insufficient data with regard to what the composition of the so called
> standardized diet optimally should be.
>
> Signs and symptoms of SBS include electrolyte disturbances;
> deficiencies of calcium, magnesium, zinc, iron, vitamin B~12~, or
> fat-soluble vitamin deficiency; malabsorption of carbohydrates,
> lactose and protein; metabolic acidosis, gastric acid hypersecretion;
> formation of cholesterol biliary calculi and renal oxalate calculi;
> and dehydration, steatorrhea, diarrhea, and weight loss. Non-specific
> approaches[^10] include increasing the absorption of sodium by sipping
> a sodium-glucose solution, reducing stomal loss by restricting water
> or low-sodium drinks. If a stoma is situated less than 100 cm along
> the jejunum, a constant negative sodium balance may necessitate
> parenteral saline supplements. Gastric antisecretory drugs or a
> somatostatin analog (off-label use) reduce jejunostomy losses in such
> patients but do not restore a positive sodium balance. Loperamide or
> codeine phosphate benefit some patients. Magnesium deficiency can
> usually be corrected by oral magnesium oxide supplements.
>
> It is important to note that **thorough nutritional management is
> necessary** in the early stages, as is replacement of excess fluid and
> electrolyte losses. Recommendations regarding the need for parenteral
> nutrition vary depending on the presence or absence of certain
> factors: the ileocecal valve, jejunum, and functional colon. Patients
> with residual small bowel of 100 cm or less usually require the
> administration of parenteral nutrition at home.
>
> The other aspect of SBS management consists of enhancing the natural
> intestinal adaptation response. Although the mechanisms of intestinal
> adaptation are not entirely understood, they can be grouped into three
> broad categories: luminal nutrition, hormonal factors, and
> pancreatobiliary secretion. Animal models of SBS have suggested
> several gut hormones are involved in postresection intestinal
> adaptation. These include enteroglucagon, glucagon peptide II,
> epidermal growth factor, growth hormone (the subject of the current
> review), cholecystokinin, gastrin, insulin, and neurotensin.[^11]
> Other therapies to enhance intestinal growth include fiber, glutamine
> (one of the components of the combination being proposed by the
> sponsor) and aminoguanidine. Although none has been approved for the
> treatment of SBS, some of the hormones, available in the clinic for
> other indications or available for human use experimentally, are used
> in the treatment of SBS. There are, however, little data on the role
> of either endogenous or exogenous hormones on intestinal adaptation in
> humans. Similarly, there are very few studies using peptides to slow
> intestinal transit (e.g. peptide YY or an analogue).[^12]

### Important Milestones in Product Development

### As mentioned above, Serostim^®^ \[somatropin (rDNA origin) for injection\] is an approved drug. Important milestones in the development of growth hormone for the indication being sought (treatment of short bowel syndrome) from meetings between FDA and the sponsor, are briefly summarized in Table 1. 

### 

###  

### 

### Table 1

### Highlights of FDA-Sponsor Meeting minutes

### 

+----------+-----------------------------------------------------------+
| *        | -   Sponsor was Cato Research                             |
| *October |                                                           |
| 19,**    | -   Pre-IND meeting to discuss research plans for the use |
|          |     of the proposed drug combination \[Glutamine (GLN) +  |
| **1994** |     Growth Hormone (GH)                                   |
|          |                                                           |
|          | -   Pre-clinical data seemed to indicate increase in gut  |
|          |     weight and length, mucosal mass, and villus height    |
|          |     and crypt depth as well as enhancement of ileal and   |
|          |     jejunal absorption of water, sodium and amino acids.  |
|          |                                                           |
|          | -   Results from a non-randomized, single center (**the   |
|          |     same center apparently involved in the pivotal        |
|          |     trial)** , investigator-sponsor IND in patients       |
|          |     considered dependent on parenteral nutrition (\> 7    |
|          |     years). An initial group of 7 patients served as      |
|          |     their own control; the experience was later expanded  |
|          |     to 24 patients. The indication was the                |
|          |     reduction/elimination of TPN in patients with         |
|          |     absorptive deficiencies, such was SBS. These initial  |
|          |     results showed \"substantial improvement in nutrient  |
|          |     absorption\" (increase in protein absorption of up to |
|          |     40%) and a decrease in fecal weight of up 33%.        |
|          |                                                           |
|          | -   Dose of GH was between 0.07 and 0.14 mg/kg/day. Dose  |
|          |     of I.V. administered GLN was between 0.45 and 0.65    |
|          |     g/kg/day for 4 weeks.                                 |
|          |                                                           |
|          | -   FDA suggested studying a different temporal sequence  |
|          |     (i.e. administering GH alone, followed by glutamine   |
|          |     therapy). It was also noted that if the oral          |
|          |     supplementation in lieu of the I.V. GLN               |
|          |     supplementation could be used, it would be simpler    |
|          |     from a regulatory standpoint. Lack of randomization   |
|          |     did not allow definitive conclusions about GH         |
|          |     activity in this indication.                          |
+----------+-----------------------------------------------------------+
| **August | -   FDA (DMEDP) letter to sponsor providing comments on   |
| 3,**     |     design of a clinical trial that would confirm         |
|          |     findings and answer questions required for approval.  |
| **1995** |                                                           |
|          | > A 3-arm randomized double blind study with 5 patients   |
|          | > receiving GH only, 5 receiving GLN only and 5 patients  |
|          | > receiving the combination was recommended.              |
+----------+-----------------------------------------------------------+
| **June   | -   FDA (DMEDP) letter to sponsor stating that the        |
| 15,**    |     revised protocol \"would suffice as *[a]{.underline}* |
|          |     pivotal study for an NDA\". The study revisions did   |
| **1997** |     not include the 3-arm design recommended by the       |
|          |     Agency.                                               |
+----------+-----------------------------------------------------------+
| **March  | -   The Sponsor (Serono Laboratories and Nutritional      |
| 28,**    |     Restart Pharmaceutical) submitted a protocol          |
|          |     amendment that changed the study design to single     |
| **2000** |     center.                                               |
+----------+-----------------------------------------------------------+
| **June   | -   Letter from FDA (DMEDP) informing sponsor that the    |
| 7,**     |     single center study design is inadequate as the sole  |
|          |     source of evidence to support a regulatory approval.  |
| **2000** |                                                           |
+----------+-----------------------------------------------------------+
| **August | -   Meeting between FDA and sponsor. The agency stated    |
| 22,**    |     that in summary, a single study, single-center for    |
|          |     this application can be filed (unless there are other |
| **2000** |     filing issues), but the hurdles are high for          |
|          |     approvability and the burden is on the sponsor to     |
|          |     prove that a single-center study is adequate. The     |
|          |     Agency also added that there is no control group and  |
|          |     results for a single-center study may not be          |
|          |     representative of outcomes in other centers due to    |
|          |     differences in standards of care. The DMEDP offered   |
|          |     its assistance for development of additional          |
|          |     protocols, proposals for bolstering enrollment, etc.  |
+----------+-----------------------------------------------------------+
| **Sep    | -   Meeting between FDA and the sponsor to discuss        |
| tember** |     results of Protocol 20317 and the planned submission  |
|          |     of a supplemental NDA for the addition of a short     |
| **6,     |     bowel syndrome indication to the Serostim^®^          |
| 2002**   |     labeling.                                             |
|          |                                                           |
|          | -   Study 20317 was a 6-week, multicenter, double-blind,  |
|          |     in-patient trial, followed by 12 weeks of outpatient  |
|          |     observation in male and female patients aged 18 to 75 |
|          |     years who were wholly or partly dependent on TPN.     |
|          |     Following a 2-week run-in phase, patients were        |
|          |     randomized to the following 3 treatment groups and    |
|          |     studied for 4 weeks:                                  |
|          |                                                           |
|          | -   \- Group 1: specialized diet including glutamine      |
|          |     (SD/GLN, n= 9)                                        |
|          |                                                           |
|          | ```{=html}                                                |
|          | <!-- -->                                                  |
|          | ```                                                       |
|          | -   Group 2: recombinant human growth hormone (0.1        |
|          |     mg/kg/day) with specialized diet excluding glutamine  |
|          |     (SD/rh-GH, n= 18)                                     |
|          |                                                           |
|          | -   Group 3: rh-GH (active, at the same dose as that      |
|          |     given to subjects in Group 2 (0.1 mg/kg/d) with       |
|          |     specialized diet including glutamine (SD/GLN/rhGH, n= |
|          |     18)                                                   |
|          |                                                           |
|          | -   Thus the specialized diet was common to the 3         |
|          |     treatment arms.                                       |
|          |                                                           |
|          | ```{=html}                                                |
|          | <!-- -->                                                  |
|          | ```                                                       |
|          | -   The **primary endpoint of efficacy** was the change   |
|          |     in TPN volume, with change in TPN calories and TPN    |
|          |     frequency as **secondary endpoints.**                 |
|          |                                                           |
|          | The Agency asked for clarification as to why the endpoint |
|          | of change in TPN volume was selected, since according to  |
|          | experts in this field, **change in nutritional status**   |
|          | is a more clinically meaningful endpoint. In response,    |
|          | the firm stated that the nutritional status of the        |
|          | patients was collected and planned to present these data  |
|          | as part of the NDA submission. Also of concern to the     |
|          | Agency was the lack of a specialized diet alone arm. Such |
|          | an omission did not allow the contribution of the         |
|          | specialized diet to the efficacy to be assessed,          |
|          | particularly since all but 3 patients were enrolled in a  |
|          | single center. It was also noted that although the        |
|          | specialized diet was fixed with regard to relative        |
|          | composition of carbohydrates, fat, and protein, the       |
|          | amount of food ingested by the patient could differ. The  |
|          | sponsor was told that information on the amount of food   |
|          | consumed at the beginning and the end of the 4-week       |
|          | treatment is needed to rule out an imbalance between      |
|          | (among) the treatment arms.                               |
|          |                                                           |
|          | **NOTE:** It is worth noting that the sponsor has         |
|          | eventually submitted the information requested at this    |
|          | pre-NDA meeting.                                          |
+----------+-----------------------------------------------------------+

### D. Other Relevant Information 

> There are at least three issues that need to be addressed. One is the
> potential toxicity of growth hormone, especially when administered
> long-term. This is briefly addressed in Sections II and VII. E. of the
> current review. The other is the primary efficacy parameters that need
> to be used to demonstrate efficacy of pharmacological agents proposed
> for the treatment of SBS. These should be clinically meaningful
> ***[nutrition]{.underline}*** endpoints and are addressed in section
> V.B. of the current review. The third is the
> *[replicability/generalizability]{.underline}* of efficacy findings;
> this issue is addressed in Section X. of the current review. The
> fourth is the role of glutamine and the \"specialized diet\" as
> components of the proposed combination. This issue is addressed in
> Section VI.D. of the current review.

### E. Important Issues with Pharmacologically Related Agents

> It is worth noting that there are no overt safety issues related to
> the class. However, one cannot conclude that \"there are no important
> issues\". Indeed, as discussed under Safety, the reviewer
> [is]{.underline} concern rh-GH may have long-term toxicity. There is
> simply no information about possible carcinogenic effects (in humans).
> The long-term safety profile of rh-GH in SBS patients, especially
> Serious Adverse Events, is simply unknown.
>
> Some important issues with pharmacologically-related agents (none has
> been approved for the sought indication) are presented below.

-   Although an exhaustive review of this issue is beyond the scope of
    the present review it is worth recapitulating that
    pharmacologically-related agents include hormones and growth
    factors. The hormones could be growth-promoting and include
    substances such as GLP-2, neurotensin, gastrin and other GHs. The
    hormones could also be motility-reducing, such as PYY. The list of
    growth factors is ever growing, but includes substances such as
    EGF/TGF-α, trefoil peptides and KGF. Brief comments on GLP-2 are
    offered at the end of this subsection.

```{=html}
<!-- -->
```
-   Infusion experiments with neurotensin in rats suggest a potential
    trophic effect on the small intestine but not the colon.[^13]

-   The physiological role of gastrin in human gut adaptation is still
    unclear but must be considered as hypergastrinemia has been
    described after a major intestinal resection. The gastric
    hyperplasia, which is associated with acid-induced inhibition, is
    mediated via gastrin but it is debatable whether this induces to
    malignancy. It has been suggested that it may not be gastrin itself
    but its intermediaries, such as glycine-extended gastric, that are
    trophic.[^14]

-   At physiological doses in man, peptide YY[^15] increases small bowel
    transit time and reduces stimulated intestinal secretion. Peptide YY
    serum levels are high in patients with a retained colon and low in
    patients with a jejunostomy, thus it may be responsible for part of
    the functional adaptation that occurs in patients with a retained
    colon. It is unlikely to be responsible for any structural changes,
    as it does not induce gut growth in rats fed only with parenteral
    nutrition.

-   Growth factors and cytokines are extracellular signaling proteins or
    peptides, the cytokines being generally considered as local
    mediators in cell-to-cell communication while the growth factors
    were originally defined on the basis of their stimulation of growth
    or cell division. EGF acts on multiple organs by several multiple
    actions, including influencing gastric acid secretion, gut growth
    and repair.

-   The mucosal integrity peptides include TGF-α and pancreatic
    secretory trypsin inhibitor, which are constitutively expressed in
    the mucosa throughout the gastrointestinal tract and function to
    maintain normal mucosal integrity. The major distribution of TGF-α
    is in the superficial (non-proliferative) zones. It may therefore be
    that its major role is to maintain cell migration and
    differentiation as opposed to proliferation.[^16]

-   The rapid-response peptides are the trefoil peptide family (e.g.
    spasmolytic polypeptide); their production is rapidly unregulated at
    sites of damage and is likely to be of particular importance in the
    early stages of mucosal repair. KGF, originally known as FGF-7, has
    been demonstrated to markedly stimulate proliferation of hepatocytes
    and epithelial cells throughout the rat gastrointestinal tract, and
    can alter crypt branching. Moreover, KGF, like EGF, also stimulates
    mucus production, but unlike EGF does not stimulate cell migration
    and is not cytoprotective.[^17]

> **GLP-2 as therapy for the short bowel syndrome**
>
> Recently, Jeppesen and his co-workers[^18] presented results of a
> pilot study using GLP-2 in 8 patients with functional short bowel
> syndrome. After an initial, extensive balance study, GLP-2 was
> administered for 35 days by a twice-daily subcutaneous injection.
> Balance studies in these patients were then repeated and GLP-2 was
> found to have resulted in significantly greater intestinal absorption
> of energy, water, and nitrogen. Patients also demonstrated increases
> in lean body mass, body weight, and reduced gastric emptying. The
> authors concluded that GKLP-2 improves intestinal absorption and
> nutrition status in short bowel patients with impaired postprandial
> GLP-2 secretion in which the terminal ileum and colon have been
> removed. The opportunities and constraints offered by the results of
> this study were recently discussed.[^19] It was concluded that the
> results of this pilot trial were modest. GLP-2 would not be considered
> cost-effective. As Jeppesen et al. note, a much greater beneficial
> effect of GLP-2 might be realized using a more optimal dose and
> duration of therapy.

## II. Clinically Relevant Findings from Chemistry, Animal Pharmacology and Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other Consultant Reviews

-   There are no CMC issues. As mentioned in the Chemistry Review by Dr.
    Maria E. Ysern, somatropin (rDNA origin) for injection is an
    approved drug, under NDA 20-604 for treatment of AIDS wasting and
    cachexia. It is further noted that the sponsor\'s claim for
    categorical exclusion for the preparation and submission of an
    Environmental Assessment is adequate. This is because the approval
    of the current application, for a new indication (short bowel
    syndrome, NDA 21-597) will not increase the use of the active
    moiety, somatropin.

```{=html}
<!-- -->
```
-   There will not be a Pharmacology/Toxicology review for the current
    application. Pharmacology and Toxicology data were reviewed By Dr.
    David H. Hertig, a Pharmacologist from HFD-510 (review dated
    February 13, 1996). The reviewer noted that a battery of in vitro
    and in vivo tests had been carried out with r-hGH. These tests
    included acute toxicity studies in mice, rats, and monkeys;
    subchronic/chronic toxicity s.c. studies for 4, 13, and 52 weeks in
    rats and s.c. studies for 4, 13, and 52 weeks in monkeys; Segment I,
    II, and III rat and Segment II rabbit reproductive tests;
    mutagenicity and special toxicity tests including irritation,
    sensitization, and antigenicity. In general, rhGH \[m\] was well
    tolerated in acute and subchronic and chronic toxicity studies with
    findings being mainly extensions of the pharmacological properties
    of growth hormone. From the standpoint of Pharmacology, the
    application under NDA 21-597 is approvable \[Dr. Jasti Choudary,
    Pharmacologist Team Leader\]. It is worth noting that
    **carcinogenicity studies have not been done with the drug. This is
    because of the expected immune response from the animals.**

```{=html}
<!-- -->
```
-   It has been shown that increased polyamine synthesis results in
    intestinal growth and maturation and that luminal nutrients promote
    the synthesis and release of certain peptides that stimulate ODC
    activity, resulting in intestinal growth. In rodent models, both GH
    and IGF-1 have been shown to increase small bowel growth after
    resection.[^20] GH mediates its trophic effects primarily through
    IGF-1. IGF-1, but not GH, has also been reported to increase mucosal
    DNA and protein levels in the jejunal mucosa of rats to reverse
    TPN-induced mucosal atrophy.[^21] The combination of IGF-1 and
    glutamine was also shown in two studies in rats to synergistically
    increase plasma IGF-1 levels, intestinal DNA, and villus growth of
    the resected small bowel.[^22] But other rodent studies do not
    support this observation.[^23] An additional important observation
    is that GH-infused, TPN-fed rats have reduced responsiveness to
    endogenous IGF-1 over time. [^24] These observations, and some
    findings in humans, question the sustained effects of GH ( see
    clinical section)

-   A study by Snibson et al.[^25] showed that overall; GH
    synergistically promotes carcinogen-induced hepatocarcinogenesis in
    both sexes of GH-transgenic mice by stimulating tumor cell
    proliferation.

-   In reality, the role of growth hormone in carcinogenesis is unclear,
    but it raises serum concentrations of insulin-like growth factor
    (IGF)-1, which is mitogenic and antiapoptotic, and results from
    in-vitro and animal studies suggest that GH may raise the risk of
    hyperplasia and malignancy.[^26]

-   A very recent study in rats suggests that the combination of
    glutamine and GH may synergistically reduce bacterial translocation
    over time in sepsis.[^27]

## III. Human Pharmacokinetics and Pharmacodynamics

> There will not be a separate Biopharm review because the sponsor has
> not submitted/presented a separate Biopharmaceutics section for
> review. The material that follows on Serostim® (rDNA human growth
> hormone for injection; rh-GH) was provided by Dr. Suliman Al-Fayoumi,
> an FDA reviewer in the Biopharmaceutics Division.

-   The absolute bioavailability of rGH following s.c. administration
    was 70 to 90%.

-   Apparent half-life of rh-GH after s.c. administration was
    significantly prolonged (3.94 [+]{.underline} 3.44 h) relative to
    that obtained after i.v. administration (0.58 [+]{.underline} 0.08
    h), which indicates that s.c. absorption is slow and rate-limiting.

-   No accumulation was observed following multiple dose administration
    of doses of

> 6 mg/d for 6 weeks. However, the **pharmacological markers**
> determined in the study (**IGF-1 and IGFBP-3**) were significantly
> higher at 6 weeks relative to the first dose.

-   The steady state volume of distribution of rh-GH in healthy subjects
    is 12.0 [+]{.underline} 1.08 L.

-   The liver plays an important role in the elimination of rGH.
    Nevertheless, rGH is primarily eliminated via kidneys where it
    undergoes glomerular filtration then it is cleaved within the renal
    cells and the peptides and amino acids are subsequently reabsorbed
    into the systemic circulation.

-   Published reports indicate that patients with chronic renal
    impairment tend to have decreased rh-GH clearance relative to normal
    healthy subjects. Similarly, patients with severe hepatic impairment
    have been reported to exhibit reduced rh-GH clearance.

-   Available evidence suggests that rGH clearance is similar between
    adults and children. However, only a limited number of pediatric
    patients were included in the clinical trials.

-   Both, the labeling for Saizen^®^ \[somatropin (rDNA for injection)\]
    and that for Serostim^®^ \[somatropin (rDNA origin) for injection\]
    state that elderly patients are more sensitive to growth hormone
    action, and may be more prone to develop adverse reactions. Thus,
    dose selection for an elderly patient should be cautious, **usually
    starting at the low end of the dosing range.**

-   Formal in vitro and in vivo drug-drug interaction studies have not
    been conducted to evaluate the drug-drug interaction potential for
    rh-GH. Recent published results suggest that rh-GH induces UDPGT and
    CYP3A enzyme systems.

-   **GH mediates its trophic effects primarily through insulin-like
    growth factor-1 (IGF-1).** In rodent models, GH and IGF-1 have been
    shown to increase small bowel growth after resection. IGF-1 and its
    receptors are expressed locally through the human and rodent small
    bowel. Endogenous GH administration increases serum

> IGF-1 levels as well as IGF-1 levels in the small intestine.

## 

## IV. Description of Clinical Data and Sources 

### 

### A. Overall Data

The present submission for Serostim^®^ for the indication treatment of
short bowel syndrome (Orphan Drug Designation 94-803), is being reviewed
under NDA 21-597. The drug, somatropin (rDNA origin) for injection, is
already approved for the indication treatment of AIDS wasting (NDA
20-604). The current submission consists of a summary, revised package
insert (Attachment 1), minutes to FDA meetings (Attachment 2), patents
information, debarment certification, user fee documents, and statement
on environmental assessment. In support of their application, the
sponsor submitted results from one pivotal trial (Study IMP20317). The
Clinical Study Report includes information on ethics, investigators and
study administrative structure, study objectives, details of results of
investigational plan (study protocol), efficacy evaluation, safety
evaluation, with discussion and overall conclusions, a list of
references and appendices.

### 

### B. Tables Listing the Clinical Trials

In this instance, there is no need for a Table listing the clinical
trials. The core of the submission consists of a clinical and
statistical study report from Protocol IMP20317: \"Randomized,
double-blind, controlled, parallel-group evaluation of the relative
efficacy and safety of recombinant human growth hormone and glutamine,
single and as a co-therapy, in the improvement of residual gut
absorptive function in patients with short bowel syndrome.\"

The trial enrolled 47 patients. Of these, 6 were discontinued
\[intercurrent illness, n=5; withdrew consent, n=1\]. A total of 41
patients was randomized into 3 groups \[Group A, n=16; Group B, n=16;
Group C, n=9; see below for identity of these 3 groups\]. The trial was
conducted at two clinical sites, Site 1 \[n= 38 patients\] at the
Brigham and Women\'s Hospital, Boston MA and Site 2 \[n= 3 patients\],
at the University of Nebraska, Omaha, NE.

### 

### C. Post-marketing Experience

> There is no marketing experience with rh-GH for short bowel syndrome
> because the sponsor is seeking a new indication for this drug in the
> United States. Also, the indication is not approved outside of the
> United States.
>
> However, the sponsor\'s Serostim^®^ was approved in
> ***[1996]{.underline}*** for the treatment of AIDS wasting or
> cachexia.[^28] Under the Adverse Reactions Section, the currently
> approved package insert includes information stating that, in
> placebo-controlled clinical trials, the most common adverse reactions
> judged to be associated with Serostim^®^ were musculoskeletal
> discomfort and increased tissue turgor (swelling, particularly of the
> hands and feet). These symptoms were generally rated by investigators
> as mild to moderate in severity and usually subsided with continued
> treatment. Discontinuations as a result of these events were rare.
> After a description of adverse events by body system, the following
> paragraph is included in the package insert. The types and incidences
> of adverse events reported in an open-label, extension trial in a
> single, foreign trial, for up to one year, were not different from, or
> greater in frequency, than those observed in the primary,
> placebo-controlled, clinical trials.
>
> Finally, the following pertinent information is included in the
> currently approved package insert. \"During post-marketing
> surveillance, cases of new onset glucose intolerance, diabetes
> mellitus and exacerbations of pre-existing diabetes mellitus have been
> reported in patients receiving Serostim^®^. Some patients developed
> diabetic ketoacidosis and diabetic coma. In some patients, these
> conditions improved when Serostim^®^ was discontinued while in others,
> the glucose intolerance persisted. Some patients necessitated
> initiation or adjustment of antidiabetic treatment while on
> Serostim^®^.\"
>
> According to the sponsor, the adverse event profile seen in the Short
> Bowel Syndrome patient population is similar to that described above.
>
> **NOTE: A consult has been sent to ODS to confirm the post-marketing
> safety profile of the drug.** Addressed in this consult will be issues
> such as off-label use in general and AEs related to the use of the
> drug in SBS as an off-label indication.

### D. Literature Review

> Literature publications used during the review included papers on the
> effect of growth hormone, other hormones, or peptides in animal models
> of short bowel syndrome, studies in humans and reviews. Among the
> latter, a very recent publication in Gastroenterology (**AGA Technical
> review on Short bowel** **Syndrome** and Intestinal
> transplantation)[^29] and a book on **Intestinal Failure**[^30] were
> particularly useful.

In addition, because of some inconsistent reports in the literature on
the role of growth hormone in the treatment of short bowel syndrome, the
sponsor was asked to identify which of the published trials have used
the Serono formulation of

rh-GH. A succinct account of the sponsor\'s May 2, 2003 to the Agency,
is given below.

-   Publications on the potential specific effects of somatropin on the
    remnant bowel were provided in sponsor\' s Attachment 1. Several
    scientific publications suggest that GH can exert an enterotrophic
    effect on the gut mucosa, an effect that may occur mainly by
    improving the life span of mature enterocytes and subsequently to
    improve the function of these enterocytes to digest nutrients, an
    effect that seems to be GH specific.

-   According to the sponsor, the entire list of 9 publications
    referenced in the May 2, 2003 submission, with the exception of the
    article and editorial by J. Scolapio (Ref. 6 in Table 2 of the
    current review) and the article by J. Szkudlarek et al.[^31] is
    supportive of their application (the use of growth hormone for the
    treatment of short bowel syndrome).

> Since Serono was not the sponsor of any of the reported studies,
> **Serono does** **not have the source documents for these
> publications.**

-   The sponsor noted that there has been one oral presentation of the
    data from the Clinical Trial submitted in NDA 21-597 at the American
    Society of Parenteral and Enteral Nutrition (ASPEN) meeting in San
    Antonio TX, on January 21, 2003. The data were presented by
    Theresa A. Byrne, DSc, one of the co-investigators in the NDA
    clinical trial.

## V. Clinical Review Methods

### A. How the Review was Conducted

Based on what the sponsor has requested in the proposed labeling, this
reviewer updated his information on the subject of short bowel syndrome.
As he has been consultant to HFD-510 (DMEDP) and has participated in
pre-NDA-related matters, he is already familiar with some of the issues
discussed at the IND level. The reviewer then examined and listed all
the evidence presented by the sponsor in support of their request. The
materials reviewed included all 8 volumes that constitute the
submission, with emphasis on the Clinical Study Report that is the
pivotal support of the application. Also considered were available
reviews and results of interactions with all other pertinent disciplines
(chemistry, pharmacology/toxicology, biopharmaceutics, and
endocrinology). These interactions were aimed at identifying issues, if
they existed, already recognized by this multidisciplinary approach.

> The review begins with a title page, identifying the sponsor, the drug
> product, and dates of submission. This information is followed by a
> concise Executive Summary, listing the main recommendations for
> regulatory action and the main issues identified in the review. The
> main objective of this part of the review is to provide the reader
> with a concise preliminary picture of the study purpose, execution,
> emerging issues identified (or re-identified), major findings and
> conclusions and efficacy and safety evaluations that led to the
> reviewer\'s recommendations for regulatory action. The organization of
> the review and a road map to its sections are found in a detailed
> Table of Contents. These sections correspond in general with the
> **\"Guideline for the Format and Content of the Clinical and
> Statistical Sections of an Application\" (CDER, FDA, July 1988).**
> Throughout the review, the reviewer\'s abstracting, paraphrasing or
> summarization of the material submitted by the sponsor as well
> reviewer-generated opinions and discussions are identified and these
> are to be differentiated from text taken directly from that submitted
> by the sponsor (usually shown in quotes) or from publications.

### B. Overview of Materials Consulted in Review

> As stated above, information from other disciplines was consulted in
> review. But the most important contribution came from publications
> related to the efficacy of growth hormone in the proposed indication,
> **treatment of short bowel syndrome.** Because literature data are
> inconsistent and because there is need to determine if the efficacy
> endpoints used in the clinical trials submitted by the sponsor in
> support of their application are adequate (clinically meaningful), the
> pertinent literature information is summarized in Table 2. The
> emphasis is on **clinically meaningful *[nutrition
> endpoints,]{.underline} ***considered by the experts as the most
> important. It is to be noted that although glutamine is one of the
> components of the proposed triple co-therapy, evaluations of the
> effect of glutamine alone are not the subject of the current
> submission or review. Therefore, information on the effects of
> glutamine alone are not included in Table 2 and will be briefly
> discussed later on in the review.

The conclusions from the publications included in Table 2 arrived at by
the authors of those publications are summarized next.

> **Ref. 1**.: GH administration accelerated protein gain and in stable
> adults patients receiving aggressive nutritional therapy without a
> significant increase in body fat or a disproportionate expansion of
> ECW. GH therapy accelerated nutrition repletion and, may shorten the
> convalescence of the malnourished patient requiring a major surgical
> procedure.
>
> **Ref. 2**.: The ability of GH to enhance amino-acid uptake from the
> gut lumen provides energy and precursors for protein synthesis in the
> gut mucosa, as well as additional substrate for anabolism in other
> organs.
>
> **Ref. 3**: GH + GLN + DIET offers a potential method for providing
> cost-effective rehabilitation of surgical patients who have the short
> bowel syndrome or other complex problem of the gastrointestinal tract.
> This therapeutic combination also may be useful to enhance bowel
> function in patients with other gastrointestinal diseases and those
> requiring extensive intestinal operations, including transplantation.
>
> **Ref. 4**: The combined administration of GH, GLN, and a modified
> diet enhanced nutrient absorption from the remnant bowel after massive
> intestinal resection. These changes occurred in a group of patients
> that previously failed to adapt to the provision of enteral nutrients.
> According to the authors, this therapy may offer an alternative to L-T
> dependence on TPN for patients with severe SBS.
>
> **Ref. 5**: 8 weeks of low-dose rhGH treatment leads to increases in
> body weight, lean body mass, and fat-free mass in patients with SBS,
> correlated to increases in IGF-1 levels \[**NOTE:** this publication
> was also the subject of an editorial \" Can the Intestine Adapt to a
> Changing Environment? By J. S. Thompson. Gastroenterology
> 113:1402-1405 (1997)\].
>
> **Ref. 6**: Although treatment with GH, GLN, and HCLF (high CHO-low
> fat) diet for 3 weeks resulted in modest improvements in electrolyte
> absorption and delayed gastric emptying, **there were no improvements
> in small bowel morphology, stool losses, or macronutrient
> absorption.**
>
> **Ref. 7**: Combined high-dose GH and GLN administered for 4 weeks,
> **did not improve absorption of fatty acids or EFA status in SBS
> patients. No changes in body weight or composition were seen when
> comparing treatment to placebo periods. The increase in LBM measured
> by DEXA scan, comparing treatment and baseline periods, was not
> accompanied by an increase in the 24-h urinary creatinine excretion
> and suspected to be associated with an accumulation of extracellular
> fluids.**
>
> **Ref. 8**: Although larger prospective, randomized, double-blind,
> controlled studies are underway to differentiate the effects of the
> components of this therapeutic approach, this study recognizes the
> **heterogeneity of this patient population** and help to identify
> patients most likely to respond to the described regimen. The regimen
> consisted of medications, a specific diet with supplements, and a
> behavior modification program. It is worth reiterating that the
> medications dosages included standard antidiarrheal and antacid
> agents, prescribed at recommended. In addition, the patients received
> GH \[**Serono Laboratories**, Norwell, MA and Eli Lilly, Indianapolis,
> IND, USA\] at an average dose of **0.09 mg/kg/d**. GH was discontinued
> upon discharge from the inpatient facility. All patients consumed a
> specific oral diet, with the percent CHO, fat, and protein and the
> type of fluids dependent upon the presence or absence of colon. While
> within the guidelines of the specific diet prescriptions, given foods
> were often adjusted based upon patient specific sensitivities,
> determined from the 24-h intake and output records, most likely to
> respond to the described noninvasive regimen.
>
> The authors of this publication note that **while the majority of the
> patients responded to the intervention with a significant reduction or
> the elimination of PN, others, despite aggressive intervention and
> monitoring, experienced minimal to no change in PN requirements. These
> patients should be considered for either intestinal transplantation or
> other therapeutic approaches.**
>
> **Ref. 9**: 3 weeks of low-dose (**subcutaneously administered 0.05
> mg/kg/d**) GH significantly improved intestinal absorption in Home
> Parenteral Nutrition (HPN)-
>
> dependent SBS patients who were on a hyperphagic western diet
> \[**NOTE:** This publication also was the subject of the Editorial
> \"Tales From the Crypt\" by J. S. Scolapio. Gastroenterology124:
> 561-564 (2003)\].

### Overview of Methods Used to Evaluate Data Quality and Integrity

> As part of the NDA submission, the sponsor presented documentation of
> the data processing section of the study workbook which contained the
> following sections: Protocol, CRF (a clean and an annotated copy).
> Panel Schemas, Form Schemas, Page Layouts, Validation Specifications
> (including Rules, Derivations and Final Validation Report), Data Entry
> Guide, General Assumptions, Data processing Notes, Correspondence,
> Audits and Quality Control. All data were subjected to electronic
> validation programs. A Clintrial^™^ DBA Report was generated to
> confirm that all records from all panels had been merged from the
> Update Table into the Data Table. Trials were conducted in accordance
> with accepted ethical standards.
>
> The sponsor explains that the follow-up data for 3 patient\'s database
> were completed and locked on 22 JULY 2002 and were selected for a 100%
> audit of all data points. All variables for these 3 subjects were
> visually checked for agreement with the final CRFs by two-person-teams
> according to standard operating procedures. With a general audit
> result of 0.0, the data passed the criteria of Cato Research Ltd. QC
> review for release (\<1:2,500). The database was unlocked on 23 JULY,
> 2002 to correct and verify 2 outstanding queries entered into the
> comments log that were found at the time of the database lock; the
> database was re-locked on the same day. During a statistical review,
> it was found that there was a page that was not entered. The sponsor
> decided to enter the omitted page post lock. The database was unlocked
> again on 08 August 2002, to enter, verify, validate and merge the page
> that had not been entered, then re-locked on the same day. According
> to the sponsor, no other trends or other questionable issues are known
> to be outstanding that would affect the planned quality for the
> clinical trial.

+------+-------+--------+----------------+---------------------------+
| **T  |       |        |                |                           |
| able |       |        |                |                           |
| 2**  |       |        |                |                           |
+------+-------+--------+----------------+---------------------------+
| **   |       |        |                |                           |
| Over |       |        |                |                           |
| view |       |        |                |                           |
| of   |       |        |                |                           |
| S    |       |        |                |                           |
| tudy |       |        |                |                           |
| E    |       |        |                |                           |
| ndpo |       |        |                |                           |
| ints |       |        |                |                           |
| Used |       |        |                |                           |
| to   |       |        |                |                           |
| Eval |       |        |                |                           |
| uate |       |        |                |                           |
| the  |       |        |                |                           |
| Ef   |       |        |                |                           |
| fect |       |        |                |                           |
| of   |       |        |                |                           |
| GH   |       |        |                |                           |
| in   |       |        |                |                           |
| the  |       |        |                |                           |
| t    |       |        |                |                           |
| reat |       |        |                |                           |
| ment |       |        |                |                           |
| of   |       |        |                |                           |
| S    |       |        |                |                           |
| BS** |       |        |                |                           |
+------+-------+--------+----------------+---------------------------+
| **S  | **    | **Main | **Efficacy     | **Summary of Results**    |
| tudy | Study | Fea    | Endpoints**    |                           |
| N    | Po    | tures/ |                | **Comments**              |
| o.** | pulat | Dose   |                |                           |
|      | ion** | of     |                |                           |
|      |       | GH**   |                |                           |
+------+-------+--------+----------------+---------------------------+
| **   | St    | Compar | Evaluated on   | -   The GH-treated        |
| 1.** | able, | ative, | Day 7 of the   |     patients gained       |
|      | nut   | open   | equilibrium    |     minimal BF but had    |
|      | ritio | -label | period and     |     significantly more    |
|      | nally |        | again 3 weeks  |     LBM (4.311 +/- 0.6 kg |
|      | c     | n = 14 | after          |     vs 1.988 +/- 0.2 kg,  |
|      | ompro |        | treatment      |     p\< or = 0.03) and    |
|      | mised | The    |                |     more protein (1.417   |
|      | pos   | SND    | -   Components |     +/- 0.3 kg vs. 0.086  |
|      | toper | pr     |     of Body    |     +/- kg, p\< or =      |
|      | ative | ovided |     Weight,    |     0.03) than did the    |
|      | pat   | ca. 50 |     which      |     SND-treated patients. |
|      | ients | kca    |     included   |                           |
|      | rece  | l/kg/d |     body fat,  | -   The increase in lean  |
|      | iving | during |     mineral    |     mass was not          |
|      | sta   | an     |     content,   |     associated with an    |
|      | ndard | i      |     lean       |     inappropriate         |
|      | n     | nitial |     (nonfat    |     expansion of ECW. In  |
|      | utrit | 7-day  |     and        |     contrast, patients    |
|      | ional | equil  |     non-mine   |     receiving SND tended  |
|      | su    | ibrium | ral-containing |     to deposit a greater  |
|      | pport | p      |     tissue)    |     proportion of body    |
|      | (hy   | eriod. |     mass,      |     weight as ECW and     |
|      | perca |        |     total body |     significantly more    |
|      | loric | 4      |     water,     |     fat than did          |
|      | diet) | pa     |                |     GH-treated patients   |
|      | for   | tients |  extracellular |     (1.004 +/- 0.3 kg vs. |
|      | s     | then   |     water      |     0.129 +/- 0.2 kg,     |
|      | evere | con    |     (ECW), and |     p\<0.05).             |
|      | g     | tinued |     body       |                           |
|      | astro | on     |     protein.   | -   GH administration     |
|      | intes | SND;   |                |     altered substrate     |
|      | tinal |        | -   Daily and  |     oxidation             |
|      | d     | 10     |     cumulative |     (respiratory quotient |
|      | ysfun | rec    |     nutrient   |     = 0.94 +/- 0.02 GH    |
|      | ction | eived, |     balance    |     vs. 1.17 +/- 0.05     |
|      |       | in     |     and        |     SND, p\< or 0.0002)   |
|      |       | add    |     substrate  |     and the use of        |
|      |       | ition, |     oxidation  |     available energy,     |
|      |       | **GH   |     studies    |     resulting in a 66%    |
|      |       | 0.14   |     determined |     increase in the       |
|      |       | mg/    |     the        |     efficacy of protein   |
|      |       | kg/d** |                |     deposition (13.37 +/- |
|      |       |        |  distribution, |     0.8 g/1000 kcal vs.   |
|      |       | **\[   |                |     8.04 g +/- 3.06       |
|      |       | recom  |    efficiency, |     g/1000 kcal, p\< or = |
|      |       | binant |     and        |     0.04).                |
|      |       | methio |                |                           |
|      |       | nyl-GH |    utilization |                           |
|      |       | (Prot  |     of         |                           |
|      |       | ropin, |     calories   |                           |
|      |       | Gene   |     for        |                           |
|      |       | ntech, |     protein,   |                           |
|      |       | South  |     fat, and   |                           |
|      |       | San    |                |                           |
|      |       | Fran   |   carbohydrate |                           |
|      |       | cisco, |                |                           |
|      |       | C      |    deposition. |                           |
|      |       | A)\]** |                |                           |
+------+-------+--------+----------------+---------------------------+
| B    |       |        |                |                           |
| yrne |       |        |                |                           |
| TA   |       |        |                |                           |
| et   |       |        |                |                           |
| al.  |       |        |                |                           |
| Anab |       |        |                |                           |
| olic |       |        |                |                           |
| the  |       |        |                |                           |
| rapy |       |        |                |                           |
| with |       |        |                |                           |
| gr   |       |        |                |                           |
| owth |       |        |                |                           |
| hor  |       |        |                |                           |
| mone |       |        |                |                           |
| acc  |       |        |                |                           |
| eler |       |        |                |                           |
| ates |       |        |                |                           |
| pro  |       |        |                |                           |
| tein |       |        |                |                           |
| gain |       |        |                |                           |
| in   |       |        |                |                           |
| surg |       |        |                |                           |
| ical |       |        |                |                           |
| pati |       |        |                |                           |
| ents |       |        |                |                           |
| r    |       |        |                |                           |
| equi |       |        |                |                           |
| ring |       |        |                |                           |
| nut  |       |        |                |                           |
| riti |       |        |                |                           |
| onal |       |        |                |                           |
| re   |       |        |                |                           |
| habi |       |        |                |                           |
| lita |       |        |                |                           |
| tion |       |        |                |                           |
| .    |       |        |                |                           |
| Ann  |       |        |                |                           |
| Surg |       |        |                |                           |
| 21   |       |        |                |                           |
| 8(4) |       |        |                |                           |
| :400 |       |        |                |                           |
| -416 |       |        |                |                           |
| (1   |       |        |                |                           |
| 993) |       |        |                |                           |
+------+-------+--------+----------------+---------------------------+
| **   | Adult | Rando  | -   Brush      | -   Treatment with        |
| 2.** | he    | mized, |     border     |     **low-dose GH**       |
|      | althy | open   |     membrane   |     resulted in a         |
|      | pat   | -label |     vesicles   |     statistically         |
|      | ients |        |     (BBMVs)    |     ***insignificant***   |
|      | adm   | n = 12 |     prepared   |     increase in           |
|      | itted |        |     by         |     amino-acid transport  |
|      | to    | -      |                |     rates in jejunal and  |
|      | the   |    For |   differential |     ileal BBMVs.          |
|      | VAH   |     3  |     c          |                           |
|      | in    |        | entrifugation. | -   High-dose GH resulted |
|      | Ga    |   days |                |     in a generalized 20%  |
|      | inesv |        | -   Ca         |     -to &0%- stimulation  |
|      | ille, | before | rrier-mediated |     of a-a transport ,    |
|      | Fl    |     su |     transport  |     whereas glucose       |
|      | orida | rgery: |     of         |     transport was not     |
|      | for   |        |     specific   |     affected..            |
|      | abdo  | a)     |     amino      |                           |
|      | minal |  daily |     acids      | -   The effects of GH     |
|      | opera |        |     measured   |     were similar in ileum |
|      | tions | subcut |     by rapid   |     and jejunum.          |
|      | such  | aneous |     mix        |                           |
|      | as    |        | ing/filtration | -   Kinetic analysis of   |
|      | Roux  |   dose |     technique  |     the transport of      |
|      | -en-Y |     of |                |     glutamine (the most   |
|      | dive  |     lo | -   Influence  |     abundant a-a in the   |
|      | rsion | w-dose |     of         |     body and the          |
|      | (harv |     h  |     ca         |     principal gut fuel)   |
|      | ested | ormone | rrier-mediated |     and the essential a-a |
|      | jeju  |        |     transport  |     leucine revealed that |
|      | num), |   (0.1 |     of         |     the increase in       |
|      | right |        |     glutamine, |     transport was caused  |
|      | hem   | mg/kg) |     leucine,   |     by a 50% increase in  |
|      | icole |        |     alanine,   |     carrier V~max~        |
|      | ctomy | b)     |     arginine,  |     consistent with an    |
|      | for   |   high |     methyl     |     increase in the       |
|      | cecal |        |     α-a        |     number of functional  |
|      | or    |   dose | minoisobutyric |     carriers in the brush |
|      | asce  |     GH |     acid and   |     border membrane.      |
|      | nding |        |     glucose by |                           |
|      | colon |   (0.2 |     BBMVs as   | -   Pooled analysis of    |
|      | le    |        |     measured   |     transport velocities  |
|      | sions | mg/kg) |     by a rapid |     demonstrated that the |
|      | (harv |        |     mix        |     total rate of a-a     |
|      | ested | *      | ing/filtration |     uptake from the gut   |
|      | i     | *Human |     technique. |     lumen was increased   |
|      | leum) | met    |                |     significantly by 35%  |
|      | .     | hionyl |                |     in GH-treated         |
|      | Co    | recom  |                |     patients.             |
|      | ntrol | binant |                |                           |
|      | je    | GH     |                |                           |
|      | junum | \[Gene |                |                           |
|      | was   | ntech, |                |                           |
|      | obt   | Inc.   |                |                           |
|      | ained | (San   |                |                           |
|      | from  | Fran   |                |                           |
|      | pat   | cisco, |                |                           |
|      | ients | CA,    |                |                           |
|      | in    | US     |                |                           |
|      | whom  | A)\]** |                |                           |
|      | n     |        |                |                           |
|      | ormal | c)  No |                |                           |
|      | je    |     Tx |                |                           |
|      | junum |        |                |                           |
|      | was   |    (co |                |                           |
|      | res   | ntrol) |                |                           |
|      | ected |        |                |                           |
|      | en    |    for |                |                           |
|      | block |     3  |                |                           |
|      | with  |        |                |                           |
|      | other |   days |                |                           |
|      | tis   |        |                |                           |
|      | sues. | before |                |                           |
|      |       |     su |                |                           |
|      |       | rgery. |                |                           |
|      |       |        |                |                           |
|      |       | All    |                |                           |
|      |       | pa     |                |                           |
|      |       | tients |                |                           |
|      |       | were   |                |                           |
|      |       | con    |                |                           |
|      |       | suming |                |                           |
|      |       | a      |                |                           |
|      |       | r      |                |                           |
|      |       | egular |                |                           |
|      |       | diet   |                |                           |
|      |       | and    |                |                           |
|      |       | re     |                |                           |
|      |       | ceived |                |                           |
|      |       | n      |                |                           |
|      |       | othing |                |                           |
|      |       | by     |                |                           |
|      |       | mouth  |                |                           |
|      |       | for    |                |                           |
|      |       | 24h    |                |                           |
|      |       | before |                |                           |
|      |       | ope    |                |                           |
|      |       | ration |                |                           |
+------+-------+--------+----------------+---------------------------+

+------+-------+--------+---+----------------+---------------------------+
| I    |       |        |   |                |                           |
| noue |       |        |   |                |                           |
| Y.   |       |        |   |                |                           |
| et   |       |        |   |                |                           |
| al.  |       |        |   |                |                           |
| Gr   |       |        |   |                |                           |
| owth |       |        |   |                |                           |
| Hor  |       |        |   |                |                           |
| mone |       |        |   |                |                           |
| Enha |       |        |   |                |                           |
| nces |       |        |   |                |                           |
| A    |       |        |   |                |                           |
| mino |       |        |   |                |                           |
| Acid |       |        |   |                |                           |
| Up   |       |        |   |                |                           |
| take |       |        |   |                |                           |
| by   |       |        |   |                |                           |
| the  |       |        |   |                |                           |
| H    |       |        |   |                |                           |
| uman |       |        |   |                |                           |
| S    |       |        |   |                |                           |
| mall |       |        |   |                |                           |
| I    |       |        |   |                |                           |
| ntes |       |        |   |                |                           |
| tine |       |        |   |                |                           |
| Ann  |       |        |   |                |                           |
| Surg |       |        |   |                |                           |
| 219  |       |        |   |                |                           |
| (6): |       |        |   |                |                           |
| 715  |       |        |   |                |                           |
| -724 |       |        |   |                |                           |
| (1   |       |        |   |                |                           |
| 994) |       |        |   |                |                           |
+------+-------+--------+---+----------------+---------------------------+
| **   | Pat   | Init   | T |                | -   The initial **balance |
| 3.** | ients | ially, | h |                |     studies** indicated   |
|      | who   | 17     | e |                |     improvement in        |
|      | had   | s      | a |                |     absorption of protein |
|      | previ | tudies | i |                |     by 39% and a 33%      |
|      | ously | were   | m |                |     decrease in stool     |
|      | unde  | per    | o |                |     output with the       |
|      | rgone | formed | f |                |     GH+GLN+DIET. In the   |
|      | exte  | in 15  | t |                |     L-T study, **40% of   |
|      | nsive | T      | h |                |     the group remain off  |
|      | bowel | PN-dep | e |                |     TPN** and **an        |
|      | rese  | endent | s |                |     additional 40% have   |
|      | ction | short  | t |                |     reduced their TPN     |
|      | for   | bowel  | u |                |     requirements,** with  |
|      | tr    | pa     | d |                |     follow up averaging a |
|      | auma, | tients | y |                |     year and the longest  |
|      | mesen | over 3 | w |                |     being over 5 years.   |
|      | teric | to 4   | a |                |                           |
|      | i     | weeks  | s |                | ```{=html}                |
|      | nfarc | in the | t |                | <!-- -->                  |
|      | tion, | cl     | o |                | ```                       |
|      | or    | inical | i |                | -   The authors speculate |
|      | in    | re     | n |                |     that this therapeutic |
|      | flamm | search | i |                |     combination (GH +     |
|      | atory | c      | t |                |     GLN + DIET) may be    |
|      | bowel | enter; | i |                |     useful to enhance     |
|      | di    | the    | a |                |     bowel function in     |
|      | sease | first  | l |                |     patients with other   |
|      | with  | week   | l |                |     gastrointestinal      |
|      | or    | served | y |                |     diseases and those    |
|      | wi    | as a   | d |                |     requiring extensive   |
|      | thout | c      | e |                |     intestinal            |
|      | co    | ontrol | t |                |     operations, including |
|      | lonic | p      | e |                |     transplantation.      |
|      | resec | eriod, | r |                |                           |
|      | tion. | and    | m |                |                           |
|      | All   | during | i |                |                           |
|      | pat   | the    | n |                |                           |
|      | ients | next 1 | e |                |                           |
|      | were  | to 3   | i |                |                           |
|      | c     | weeks, | f |                |                           |
|      | hroni | the    | G |                |                           |
|      | cally | sp     | H |                |                           |
|      | depe  | ecific | o |                |                           |
|      | ndent | tre    | r |                |                           |
|      | on    | atment | n |                |                           |
|      | s     | was    | u |                |                           |
|      | pecia | admini | t |                |                           |
|      | lized | stered | r |                |                           |
|      | n     | and    | i |                |                           |
|      | utrit | eval   | e |                |                           |
|      | ional | uated. | n |                |                           |
|      | sup   | Thro   | t |                |                           |
|      | port. | ughout | s |                |                           |
|      | All   | the    | , |                |                           |
|      | pat   | study, | g |                |                           |
|      | ients | food   | i |                |                           |
|      | were  | of     | v |                |                           |
|      | able  | known  | e |                |                           |
|      | to    | compo  | n |                |                           |
|      | tol   | sition | a |                |                           |
|      | erate | was    | l |                |                           |
|      | *ad   | pro    | o |                |                           |
|      | lib   | vided. | n |                |                           |
|      | itum* |        | e |                |                           |
|      | oral  | The    | o |                |                           |
|      | diet, | tre    | r |                |                           |
|      | but   | atment | t |                |                           |
|      | wi    | was    | o |                |                           |
|      | thout | ex     | g |                |                           |
|      | paren | panded | e |                |                           |
|      | teral | to 47  | t |                |                           |
|      | su    | adults | h |                |                           |
|      | pport | (25    | e |                |                           |
|      | they  | men,   | r |                |                           |
|      | were  | 22     | , |                |                           |
|      | u     | women) | c |                |                           |
|      | nable | with   | o |                |                           |
|      | to    | short  | u |                |                           |
|      | adequ | bowel  | l |                |                           |
|      | ately | syn    | d |                |                           |
|      | mai   | drome, | e |                |                           |
|      | ntain | dep    | n |                |                           |
|      | hydr  | ending | h |                |                           |
|      | ation | on TPN | a |                |                           |
|      | a     | for 6  | n |                |                           |
|      | nd/or | +- 1   | c |                |                           |
|      | n     | years. | e |                |                           |
|      | utrit |        | a |                |                           |
|      | ional | After  | b |                |                           |
|      | st    | 28     | s |                |                           |
|      | atus. | days   | o |                |                           |
|      |       | of     | r |                |                           |
|      |       | th     | p |                |                           |
|      |       | erapy, | t |                |                           |
|      |       | the    | i |                |                           |
|      |       | pa     | o |                |                           |
|      |       | tients | n |                |                           |
|      |       | were   | f |                |                           |
|      |       | disc   | r |                |                           |
|      |       | harged | o |                |                           |
|      |       | on     | m |                |                           |
|      |       | only   | t |                |                           |
|      |       | GLN    | h |                |                           |
|      |       |        | e |                |                           |
|      |       | **GH:  | r |                |                           |
|      |       | 0.14   | e |                |                           |
|      |       | mg/    | m |                |                           |
|      |       | kg/d** | n |                |                           |
|      |       |        | a |                |                           |
|      |       | **\    | n |                |                           |
|      |       | [recom | t |                |                           |
|      |       | binant | s |                |                           |
|      |       | met    | m |                |                           |
|      |       | hionyl | a |                |                           |
|      |       | GH,    | l |                |                           |
|      |       | Pro    | l |                |                           |
|      |       | topin, | b |                |                           |
|      |       | Gene   | o |                |                           |
|      |       | ntech, | w |                |                           |
|      |       | Inc.,  | e |                |                           |
|      |       | San    | l |                |                           |
|      |       | Fran   | a |                |                           |
|      |       | cisco, | f |                |                           |
|      |       | CA\]** | t |                |                           |
|      |       |        | e |                |                           |
|      |       | **GLN  | r |                |                           |
|      |       | :      | m |                |                           |
|      |       | supple | a |                |                           |
|      |       | mental | s |                |                           |
|      |       | pare   | s |                |                           |
|      |       | nteral | i |                |                           |
|      |       | and    | v |                |                           |
|      |       | /or**  | e |                |                           |
|      |       |        | i |                |                           |
|      |       | **e    | n |                |                           |
|      |       | nteral | t |                |                           |
|      |       | L-GLN  | e |                |                           |
|      |       | (given | s |                |                           |
|      |       | at an  | t |                |                           |
|      |       | a      | i |                |                           |
|      |       | verage | n |                |                           |
|      |       | dose   | a |                |                           |
|      |       | of 0.6 | l |                |                           |
|      |       | g      | r |                |                           |
|      |       | /kg/d; | e |                |                           |
|      |       | Aji    | s |                |                           |
|      |       | nomoto | e |                |                           |
|      |       | USA,   | c |                |                           |
|      |       | Ra     | t |                |                           |
|      |       | leigh, | i |                |                           |
|      |       | NC)**  | o |                |                           |
|      |       |        | n |                |                           |
|      |       | \+     | . |                |                           |
|      |       | DIET.  |   |                |                           |
|      |       |        | T |                |                           |
|      |       |        | h |                |                           |
|      |       |        | r |                |                           |
|      |       |        | o |                |                           |
|      |       |        | u |                |                           |
|      |       |        | g |                |                           |
|      |       |        | h |                |                           |
|      |       |        | o |                |                           |
|      |       |        | u |                |                           |
|      |       |        | t |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | u |                |                           |
|      |       |        | d |                |                           |
|      |       |        | y |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | l |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | o |                |                           |
|      |       |        | o |                |                           |
|      |       |        | l |                |                           |
|      |       |        | w |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | c |                |                           |
|      |       |        | o |                |                           |
|      |       |        | l |                |                           |
|      |       |        | l |                |                           |
|      |       |        | e |                |                           |
|      |       |        | 3 |                |                           |
|      |       |        | c |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | y |                |                           |
|      |       |        | z |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | t |                |                           |
|      |       |        | o |                |                           |
|      |       |        | d |                |                           |
|      |       |        | e |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | m |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | e |                |                           |
|      |       |        | a |                |                           |
|      |       |        | b |                |                           |
|      |       |        | s |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | p |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        | a |                |                           |
|      |       |        | c |                |                           |
|      |       |        | r |                |                           |
|      |       |        | o |                |                           |
|      |       |        | s |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        | m |                |                           |
|      |       |        | a |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | g |                |                           |
|      |       |        | b |                |                           |
|      |       |        | o |                |                           |
|      |       |        | w |                |                           |
|      |       |        | e |                |                           |
|      |       |        | l |                |                           |
|      |       |        | . |                |                           |
|      |       |        |   |                |                           |
|      |       |        | T |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        | e |                |                           |
|      |       |        | f |                |                           |
|      |       |        | f |                |                           |
|      |       |        | e |                |                           |
|      |       |        | c |                |                           |
|      |       |        | t |                |                           |
|      |       |        | o |                |                           |
|      |       |        | f |                |                           |
|      |       |        | a |                |                           |
|      |       |        | h |                |                           |
|      |       |        | i |                |                           |
|      |       |        | g |                |                           |
|      |       |        | h |                |                           |
|      |       |        | - |                |                           |
|      |       |        | c |                |                           |
|      |       |        | a |                |                           |
|      |       |        | r |                |                           |
|      |       |        | b |                |                           |
|      |       |        | o |                |                           |
|      |       |        | h |                |                           |
|      |       |        | y |                |                           |
|      |       |        | d |                |                           |
|      |       |        | r |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | , |                |                           |
|      |       |        | l |                |                           |
|      |       |        | o |                |                           |
|      |       |        | w |                |                           |
|      |       |        | - |                |                           |
|      |       |        | f |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        | d |                |                           |
|      |       |        | i |                |                           |
|      |       |        | e |                |                           |
|      |       |        | t |                |                           |
|      |       |        | ( |                |                           |
|      |       |        | D |                |                           |
|      |       |        | I |                |                           |
|      |       |        | E |                |                           |
|      |       |        | T |                |                           |
|      |       |        | ) |                |                           |
|      |       |        | , |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        | a |                |                           |
|      |       |        | m |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | o |                |                           |
|      |       |        | a |                |                           |
|      |       |        | c |                |                           |
|      |       |        | i |                |                           |
|      |       |        | d |                |                           |
|      |       |        | g |                |                           |
|      |       |        | l |                |                           |
|      |       |        | u |                |                           |
|      |       |        | t |                |                           |
|      |       |        | a |                |                           |
|      |       |        | m |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | e |                |                           |
|      |       |        | ( |                |                           |
|      |       |        | G |                |                           |
|      |       |        | L |                |                           |
|      |       |        | N |                |                           |
|      |       |        | ) |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        | G |                |                           |
|      |       |        | H |                |                           |
|      |       |        | a |                |                           |
|      |       |        | d |                |                           |
|      |       |        | m |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | i |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        | e |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | c |                |                           |
|      |       |        | o |                |                           |
|      |       |        | m |                |                           |
|      |       |        | b |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        | w |                |                           |
|      |       |        | i |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        | o |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | a |                |                           |
|      |       |        | p |                |                           |
|      |       |        | i |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | ( |                |                           |
|      |       |        | G |                |                           |
|      |       |        | H |                |                           |
|      |       |        |   |                |                           |
|      |       |        | + |                |                           |
|      |       |        | G |                |                           |
|      |       |        | L |                |                           |
|      |       |        | N |                |                           |
|      |       |        |   |                |                           |
|      |       |        | + |                |                           |
|      |       |        | D |                |                           |
|      |       |        | I |                |                           |
|      |       |        | E |                |                           |
|      |       |        | T |                |                           |
|      |       |        | ) |                |                           |
|      |       |        | w |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | e |                |                           |
|      |       |        | v |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | u |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | . |                |                           |
+------+-------+--------+---+----------------+---------------------------+
| By   |       |        |   |                |                           |
| rne, |       |        |   |                |                           |
| TA.  |       |        |   |                |                           |
| A    |       |        |   |                |                           |
| New  |       |        |   |                |                           |
| t    |       |        |   |                |                           |
| reat |       |        |   |                |                           |
| ment |       |        |   |                |                           |
| for  |       |        |   |                |                           |
| Pati |       |        |   |                |                           |
| ents |       |        |   |                |                           |
| with |       |        |   |                |                           |
| S    |       |        |   |                |                           |
| hort |       |        |   |                |                           |
| -B   |       |        |   |                |                           |
| owel |       |        |   |                |                           |
| S    |       |        |   |                |                           |
| yndr |       |        |   |                |                           |
| ome: |       |        |   |                |                           |
| Gr   |       |        |   |                |                           |
| owth |       |        |   |                |                           |
| Horm |       |        |   |                |                           |
| one, |       |        |   |                |                           |
| Gl   |       |        |   |                |                           |
| utam |       |        |   |                |                           |
| ine, |       |        |   |                |                           |
| and  |       |        |   |                |                           |
| a    |       |        |   |                |                           |
| Modi |       |        |   |                |                           |
| fied |       |        |   |                |                           |
| D    |       |        |   |                |                           |
| iet. |       |        |   |                |                           |
| Ann  |       |        |   |                |                           |
| Surg |       |        |   |                |                           |
| 222  |       |        |   |                |                           |
| (3): |       |        |   |                |                           |
| 243  |       |        |   |                |                           |
| -255 |       |        |   |                |                           |
| (1   |       |        |   |                |                           |
| 995) |       |        |   |                |                           |
+------+-------+--------+---+----------------+---------------------------+
| **   | 10    | Pa     | T |                | -   Tx with diet alone    |
| 4.** | pat   | tients | h |                |     did not influence     |
|      | ients | were   | e |                |     nutrient absorption   |
|      | (5    | ad     | e |                |     or stool output.      |
|      | fem   | mitted | f |                |                           |
|      | ales, | to the | f |                | -   3 weeks Tx with GH,   |
|      | 5     | Cl     | i |                |     GLN, and a modified   |
|      | m     | inical | c |                |     diet **increased      |
|      | ales) | Re     | i |                |     total caloric         |
|      | with  | search | e |                |     absorption** from     |
|      | s     | Center | n |                |     60.1% to 74.3 % (p\<  |
|      | evere | for a  | c |                |     or = 0.003),          |
|      | SBS   | 28-day | y |                |     **protein             |
|      | who   | p      | o |                |     absorption** from     |
|      | had   | eriod. | f |                |     48.8 to 63.0% (p\< or |
|      | unde  | The    | n |                |     = 0.006), **and CHO   |
|      | rgone | first  | e |                |     absorption** from     |
|      | exte  | week   | t |                |     60.0 to 81.5 % (p \<  |
|      | nsive | served | n |                |     or = 0.02).           |
|      | small | as a   | u |                |                           |
|      | bowel | c      | t |                | -   Fat absorption did    |
|      | rese  | ontrol | r |                |     not change (61.0 to   |
|      | ction | period | i |                |     60.3%)                |
|      | with  | when   | e |                |                           |
|      | or    | nutri  | n |                | -   There was also a      |
|      | wi    | tional | t |                |     significant increase  |
|      | thout | (e     | a |                |     of water and sodium   |
|      | co    | nteral | b |                |     absorption.           |
|      | lonic | and    | s |                |                           |
|      | resec | paren  | o |                | -   The above-described   |
|      | tion, | teral) | r |                |     absorptive changes    |
|      | who   | and    | p |                |     resulted in a         |
|      | were  | m      | t |                |     decrease in stool     |
|      | ambul | edical | i |                |     output (1,783 g/d     |
|      | atory | mana   | o |                |     control period vs.    |
|      | and   | gement | n |                |     1,308 g/d third week  |
|      | clini | sim    | ( |                |     of treatment, p\< or  |
|      | cally | ulated | p |                |     = 0.05)               |
|      | st    | usual  | e |                |                           |
|      | able. | home   | r |                |                           |
|      |       | th     | c |                |                           |
|      | Other | erapy. | e |                |                           |
|      | chara | There  | n |                |                           |
|      | cteri | after, | t |                |                           |
|      | stics | 8 pts. | a |                |                           |
|      | of    | re     | b |                |                           |
|      | the   | ceived | s |                |                           |
|      | study | exo    | o |                |                           |
|      | popul | genous | r |                |                           |
|      | ation | GH,    | b |                |                           |
|      | were  | supple | e |                |                           |
|      | as    | mental | d |                |                           |
|      | desc  | GLN,   | ) |                |                           |
|      | ribed | and a  | f |                |                           |
|      | a     | mo     | o |                |                           |
|      | bove. | dified | r |                |                           |
|      |       | hig    | t |                |                           |
|      |       | h-CHO, | o |                |                           |
|      |       | high   | t |                |                           |
|      |       | -fiber | a |                |                           |
|      |       | diet.; | l |                |                           |
|      |       | 2 pts. | c |                |                           |
|      |       | were   | a |                |                           |
|      |       | t      | l |                |                           |
|      |       | reated | o |                |                           |
|      |       | with   | r |                |                           |
|      |       | the    | i |                |                           |
|      |       | mo     | e |                |                           |
|      |       | dified | s |                |                           |
|      |       | diet   | , |                |                           |
|      |       | alone. | p |                |                           |
|      |       |        | r |                |                           |
|      |       | The Gh | o |                |                           |
|      |       | was a  | t |                |                           |
|      |       | recom  | e |                |                           |
|      |       | binant | i |                |                           |
|      |       | methio | n |                |                           |
|      |       | nyl-GH | , |                |                           |
|      |       | **     | f |                |                           |
|      |       | \[Prot | a |                |                           |
|      |       | oprin, | t |                |                           |
|      |       | Gen    | , |                |                           |
|      |       | entech | C |                |                           |
|      |       | Inc.)  | H |                |                           |
|      |       | at a   | O |                |                           |
|      |       | dose   | , |                |                           |
|      |       | 0.14   | w |                |                           |
|      |       | mg/kg/ | a |                |                           |
|      |       | d.\]** | t |                |                           |
|      |       |        | e |                |                           |
|      |       | GLN    | r |                |                           |
|      |       | was    | , |                |                           |
|      |       | admini | a |                |                           |
|      |       | stered | n |                |                           |
|      |       | at an  | d |                |                           |
|      |       | a      | s |                |                           |
|      |       | verage | o |                |                           |
|      |       | pare   | d |                |                           |
|      |       | nteral | i |                |                           |
|      |       | dose   | u |                |                           |
|      |       | of     | m |                |                           |
|      |       | 0.42   | w |                |                           |
|      |       | g/kg/d | a |                |                           |
|      |       | or     | s |                |                           |
|      |       | given  | c |                |                           |
|      |       | as     | a |                |                           |
|      |       | L-glu  | l |                |                           |
|      |       | p      | c |                |                           |
|      |       | owder, | u |                |                           |
|      |       | at the | l |                |                           |
|      |       | e      | a |                |                           |
|      |       | nteral | t |                |                           |
|      |       | dose   | e |                |                           |
|      |       | of     | d |                |                           |
|      |       | 0.63   | f |                |                           |
|      |       | g      | r |                |                           |
|      |       | /kg/d. | o |                |                           |
|      |       |        | m |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        | m |                |                           |
|      |       |        | e |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | u |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | n |                |                           |
|      |       |        | u |                |                           |
|      |       |        | t |                |                           |
|      |       |        | r |                |                           |
|      |       |        | i |                |                           |
|      |       |        | e |                |                           |
|      |       |        | n |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | t |                |                           |
|      |       |        | a |                |                           |
|      |       |        | k |                |                           |
|      |       |        | e |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | o |                |                           |
|      |       |        | o |                |                           |
|      |       |        | l |                |                           |
|      |       |        | l |                |                           |
|      |       |        | o |                |                           |
|      |       |        | s |                |                           |
|      |       |        | s |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | . |                |                           |
+------+-------+--------+---+----------------+---------------------------+
| By   |       |        |   |                |                           |
| rne, |       |        |   |                |                           |
| TA,  |       |        |   |                |                           |
| et   |       |        |   |                |                           |
| al.  |       |        |   |                |                           |
| Gr   |       |        |   |                |                           |
| owth |       |        |   |                |                           |
| Horm |       |        |   |                |                           |
| one, |       |        |   |                |                           |
| Gl   |       |        |   |                |                           |
| utam |       |        |   |                |                           |
| ine, |       |        |   |                |                           |
| and  |       |        |   |                |                           |
| a    |       |        |   |                |                           |
| Modi |       |        |   |                |                           |
| fied |       |        |   |                |                           |
| D    |       |        |   |                |                           |
| iet) |       |        |   |                |                           |
| Enh  |       |        |   |                |                           |
| ance |       |        |   |                |                           |
| Nutr |       |        |   |                |                           |
| ient |       |        |   |                |                           |
| Ab   |       |        |   |                |                           |
| sorp |       |        |   |                |                           |
| tion |       |        |   |                |                           |
| in   |       |        |   |                |                           |
| Pati |       |        |   |                |                           |
| ents |       |        |   |                |                           |
| With |       |        |   |                |                           |
| Se   |       |        |   |                |                           |
| vere |       |        |   |                |                           |
| S    |       |        |   |                |                           |
| hort |       |        |   |                |                           |
| -B   |       |        |   |                |                           |
| owel |       |        |   |                |                           |
| S    |       |        |   |                |                           |
| yndr |       |        |   |                |                           |
| ome. |       |        |   |                |                           |
| J    |       |        |   |                |                           |
| Par  |       |        |   |                |                           |
| Ent  |       |        |   |                |                           |
| Nutr |       |        |   |                |                           |
| 19   |       |        |   |                |                           |
| (4): |       |        |   |                |                           |
| 296  |       |        |   |                |                           |
| -302 |       |        |   |                |                           |
| (1   |       |        |   |                |                           |
| 995) |       |        |   |                |                           |
+------+-------+--------+---+----------------+---------------------------+
| **   | 10    | This   | A |                | -   This **well-designed  |
| 5.** | pat   | was a  | b |                |     and apparently well-  |
|      | ients | p      | s |                |     executed study** is   |
|      | (3F,  | lacebo | o |                |     of interest. The      |
|      | 7M)   | -contr | r |                |     authors set to        |
|      | with  | olled, | p |                |     investigate the       |
|      | SBS   | rando  | t |                |     effects of low dose   |
|      | for   | mized, | i |                |     rhGH (from a source   |
|      | more  | double | v |                |     different from that   |
|      | than  | blind, | e |                |     from the sponsor of   |
|      | 1     | cro    | c |                |     the present NDA) on   |
|      | year  | ssover | a |                |     body composition and  |
|      | be    | cl     | p |                |     absorptive capacity   |
|      | cause | inical | a |                |     in patients with SBS  |
|      | of    | trial. | c |                |     from Crohn\'s         |
|      | Cro   |        | i |                |     disease.              |
|      | hn\'s | 10     | t |                |                           |
|      | dis   | pts.   | y |                | -   Low-dose rhGH         |
|      | ease. | were   | a |                |     **doubled serum       |
|      | Some  | t      | n |                |     concentrations of     |
|      | pts.  | reated | d |                |     IGF-1** and increased |
|      | had   | with   | b |                |     body weight, lean     |
|      | some  | daily  | i |                |     body mass, and total  |
|      | blood | subcut | o |                |     body potassium by 5%. |
|      | bi    | aneous | c |                |                           |
|      | ochem | doses  | h |                | -   Fat-free mass and     |
|      | istry | of     | e |                |     total body water      |
|      | abno  | **     | m |                |     increased by 6% (p =  |
|      | rmali | rhGH/p | i |                |     0.008).               |
|      | ties. | lacebo | c |                |                           |
|      | All   | (0.5   | a |                | -   **Increased in IGF-1  |
|      | had   | i      | l |                |     levels correlated     |
|      | n     | nterna | p |                |     with increase in      |
|      | ormal | tional | a |                |     fat-free mass**       |
|      | fa    | units  | r |                |                           |
|      | sting | /      | a |                | > (r = 0.77, p\< 0.02).   |
|      | serum | kg^-1^ | m |                |                           |
|      | gl    | per    | e |                | -   No significant        |
|      | ucose | we     | t |                |     changes in absorptive |
|      | conce | ek^-1^ | e |                |     capacity of water,    |
|      | ntrat | =**    | r |                |     energy, or protein    |
|      | ions. |        | s |                |     were detected.        |
|      | Al l  | *      | w |                |                           |
|      |       | *0.024 | e |                |                           |
|      | exhi  | mg/    | r |                |                           |
|      | bited | kg^-1^ | e |                |                           |
|      | n     | per    | i |                |                           |
|      | ormal | day    | n |                |                           |
|      | 24-h  | ^-1^** | v |                |                           |
|      | GH    |        | e |                |                           |
|      | prof  | **     | s |                |                           |
|      | iles, | Source | t |                |                           |
|      | with  | of GH: | i |                |                           |
|      | ma    | Geno   | g |                |                           |
|      | ximum | tropin | a |                |                           |
|      | peak  | Kabi   | t |                |                           |
|      | v     | Phar   | e |                |                           |
|      | alues | macia, | d |                |                           |
|      | of \> | Stoc   | i |                |                           |
|      | 5     | kholm, | n |                |                           |
|      | mil   | Swe    | a |                |                           |
|      | liuni | den)** | m |                |                           |
|      | ts/L. |        | e |                |                           |
|      | Daily | The    | t |                |                           |
|      | fe    | lo     | a |                |                           |
|      | cal/s | w-dose | b |                |                           |
|      | tomal | rhGH/p | o |                |                           |
|      | ou    | lacebo | l |                |                           |
|      | tputs | was    | i |                |                           |
|      | were  | admini | c |                |                           |
|      | 2.9   | stered | w |                |                           |
|      | kg    | daily, | a |                |                           |
|      | (r    | su     | r |                |                           |
|      | ange, | bcutan | d |                |                           |
|      | 0.9   | eously | b |                |                           |
|      | to    | during | e |                |                           |
|      | 5.8   | 8      | f |                |                           |
|      | kg).  | weeks, | o |                |                           |
|      | All   | sep    | r |                |                           |
|      | re3q  | arated | e |                |                           |
|      | uired | by a   | T |                |                           |
|      | oral  | w      | x |                |                           |
|      | or    | ashout | a |                |                           |
|      | paren | period | n |                |                           |
|      | teral | of at  | d |                |                           |
|      | fluid | least  | d |                |                           |
|      | su    | 12     | u |                |                           |
|      | bstit | weeks. | r |                |                           |
|      | ution |        | i |                |                           |
|      | in    |        | n |                |                           |
|      | c     |        | g |                |                           |
|      | ombin |        | f |                |                           |
|      | ation |        | i |                |                           |
|      | with  |        | r |                |                           |
|      | ele   |        | s |                |                           |
|      | ctrol |        | t |                |                           |
|      | ytes, |        | a |                |                           |
|      | vita  |        | n |                |                           |
|      | mins, |        | d |                |                           |
|      | and   |        | l |                |                           |
|      | mine  |        | a |                |                           |
|      | rals. |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | w |                |                           |
|      |       |        | e |                |                           |
|      |       |        | e |                |                           |
|      |       |        | k |                |                           |
|      |       |        | o |                |                           |
|      |       |        | f |                |                           |
|      |       |        | T |                |                           |
|      |       |        | x |                |                           |
|      |       |        | . |                |                           |
|      |       |        |   |                |                           |
|      |       |        | B |                |                           |
|      |       |        | o |                |                           |
|      |       |        | d |                |                           |
|      |       |        | y |                |                           |
|      |       |        | c |                |                           |
|      |       |        | o |                |                           |
|      |       |        | m |                |                           |
|      |       |        | p |                |                           |
|      |       |        | o |                |                           |
|      |       |        | s |                |                           |
|      |       |        | i |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        | w |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | d |                |                           |
|      |       |        | e |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | m |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | b |                |                           |
|      |       |        | y |                |                           |
|      |       |        | D |                |                           |
|      |       |        | E |                |                           |
|      |       |        | X |                |                           |
|      |       |        | A |                |                           |
|      |       |        | - |                |                           |
|      |       |        | S |                |                           |
|      |       |        | c |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | ( |                |                           |
|      |       |        | L |                |                           |
|      |       |        | u |                |                           |
|      |       |        | n |                |                           |
|      |       |        | a |                |                           |
|      |       |        | r |                |                           |
|      |       |        | D |                |                           |
|      |       |        | P |                |                           |
|      |       |        | X |                |                           |
|      |       |        | , |                |                           |
|      |       |        | S |                |                           |
|      |       |        | c |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | e |                |                           |
|      |       |        | x |                |                           |
|      |       |        | p |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | t |                |                           |
|      |       |        | M |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | i |                |                           |
|      |       |        | c |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | , |                |                           |
|      |       |        | H |                |                           |
|      |       |        | e |                |                           |
|      |       |        | l |                |                           |
|      |       |        | s |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | g |                |                           |
|      |       |        | b |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | g |                |                           |
|      |       |        | , |                |                           |
|      |       |        | S |                |                           |
|      |       |        | w |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | e |                |                           |
|      |       |        | n |                |                           |
|      |       |        | ) |                |                           |
|      |       |        | , |                |                           |
|      |       |        | i |                |                           |
|      |       |        | m |                |                           |
|      |       |        | p |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | c |                |                           |
|      |       |        | e |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | y |                |                           |
|      |       |        | s |                |                           |
|      |       |        | i |                |                           |
|      |       |        | s |                |                           |
|      |       |        | , |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        | w |                |                           |
|      |       |        | h |                |                           |
|      |       |        | o |                |                           |
|      |       |        | l |                |                           |
|      |       |        | e |                |                           |
|      |       |        | b |                |                           |
|      |       |        | o |                |                           |
|      |       |        | d |                |                           |
|      |       |        | y |                |                           |
|      |       |        | p |                |                           |
|      |       |        | o |                |                           |
|      |       |        | t |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | s |                |                           |
|      |       |        | i |                |                           |
|      |       |        | u |                |                           |
|      |       |        | m |                |                           |
|      |       |        | c |                |                           |
|      |       |        | o |                |                           |
|      |       |        | u |                |                           |
|      |       |        | n |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | g |                |                           |
|      |       |        | . |                |                           |
+------+-------+--------+---+----------------+---------------------------+
| E    |       |        |   |                |                           |
| lleg |       |        |   |                |                           |
| ard, |       |        |   |                |                           |
| L.   |       |        |   |                |                           |
| Low- |       |        |   |                |                           |
| Dose |       |        |   |                |                           |
| Rec  |       |        |   |                |                           |
| ombi |       |        |   |                |                           |
| nant |       |        |   |                |                           |
| H    |       |        |   |                |                           |
| uman |       |        |   |                |                           |
| Gr   |       |        |   |                |                           |
| owth |       |        |   |                |                           |
| Hor  |       |        |   |                |                           |
| mone |       |        |   |                |                           |
| I    |       |        |   |                |                           |
| ncre |       |        |   |                |                           |
| ases |       |        |   |                |                           |
| Body |       |        |   |                |                           |
| We   |       |        |   |                |                           |
| ight |       |        |   |                |                           |
| and  |       |        |   |                |                           |
| Lean |       |        |   |                |                           |
| Body |       |        |   |                |                           |
| Mass |       |        |   |                |                           |
| in   |       |        |   |                |                           |
| Pati |       |        |   |                |                           |
| ents |       |        |   |                |                           |
| with |       |        |   |                |                           |
| S    |       |        |   |                |                           |
| hort |       |        |   |                |                           |
| B    |       |        |   |                |                           |
| owel |       |        |   |                |                           |
| S    |       |        |   |                |                           |
| yndr |       |        |   |                |                           |
| ome. |       |        |   |                |                           |
| Ann  |       |        |   |                |                           |
| Surg |       |        |   |                |                           |
| 225  |       |        |   |                |                           |
| (1): |       |        |   |                |                           |
| 8    |       |        |   |                |                           |
| 8-96 |       |        |   |                |                           |
| (1   |       |        |   |                |                           |
| 997) |       |        |   |                |                           |
+------+-------+--------+---+----------------+---------------------------+
| **   | 8     | D-B,   | T |                | -   **rhGH *transiently*  |
| 6.** | pat   | PL     | h |                |     increased body        |
|      | ients | -contr | e |                |     weight, significantly |
|      | (6    | olled, | w |                |     but modestly          |
|      | men   | rando  | e |                |     increased the         |
|      | and 2 | mized, | i |                |     absorption of sodium  |
|      | w     | 6      | g |                |     and potassium and     |
|      | omen) | -week, | h |                |     decreased gastric     |
|      | with  | cros   | t |                |     emptying.**           |
|      | SBS   | sover. | , |                |                           |
|      | who   |        | B |                | -   **The assimilation of |
|      | were  | Pts.   | M |                |     macronutrients, stool |
|      | depe  | were   | R |                |     volumes and           |
|      | ndent | ad     | , |                |     morphometry of small  |
|      | on    | mitted | n |                |     bowel mucosa were not |
|      | L-T   | to     | u |                |     statistically         |
|      | HPN   | Mayo   | t |                |     different in the 2    |
|      | (home | Cli    | r |                |     treatment arms.**     |
|      | paren | nic\'s | i |                |                           |
|      | teral | GCRC   | e |                |                           |
|      | nutri |        | n |                |                           |
|      | tion) | For 4d | t |                |                           |
|      | for   | on 3   | a |                |                           |
|      | an    | se     | n |                |                           |
|      | av    | parate | d |                |                           |
|      | erage | occa   | e |                |                           |
|      | of    | sions, | l |                |                           |
|      | 12.9  | 21     | e |                |                           |
|      | y     | days   | c |                |                           |
|      | ears, | apart. | t |                |                           |
|      | with  |        | r |                |                           |
|      | mean  | Active | o |                |                           |
|      | res   | Tx was | l |                |                           |
|      | idual | **GH** | y |                |                           |
|      | small |        | t |                |                           |
|      | bowel | *      | e |                |                           |
|      | l     | *(0.14 | b |                |                           |
|      | ength | mg.    | a |                |                           |
|      | of 71 | k      | l |                |                           |
|      | cm..  | g^-1^. | a |                |                           |
|      | All   | d^-1^  | n |                |                           |
|      | pat   | ),**   | c |                |                           |
|      | ients |        | e |                |                           |
|      | were  | *      | , |                |                           |
|      | able  | *\[Eli | s |                |                           |
|      | to    | Lilly  | e |                |                           |
|      | eat   | Co.,   | r |                |                           |
|      | food  | I      | u |                |                           |
|      | by    | ndiana | m |                |                           |
|      | mouth | polis, | i |                |                           |
|      | but   | IN\]** | n |                |                           |
|      | were  |        | s |                |                           |
|      | u     | *      | u |                |                           |
|      | nable | *and** | l |                |                           |
|      | to    |        | i |                |                           |
|      | mai   | **GLN  | n |                |                           |
|      | ntain | (0.63  | - |                |                           |
|      | hydr  | g. kg  | l |                |                           |
|      | ation | ^-1^.  | i |                |                           |
|      | or    | d^-1^) | k |                |                           |
|      | ade   | and a  | e |                |                           |
|      | quate | high   | g |                |                           |
|      | nutr  | C      | r |                |                           |
|      | ition | HO-low | o |                |                           |
|      | (or   | fat    | w |                |                           |
|      | both) | (HCLF) | t |                |                           |
|      | wi    | diet   | h |                |                           |
|      | thout | for 21 | f |                |                           |
|      | paren | d      | a |                |                           |
|      | teral | ays.** | c |                |                           |
|      | nutr  |        | t |                |                           |
|      | ition |        | o |                |                           |
|      | sup   |        | r |                |                           |
|      | port. |        | 1 |                |                           |
|      |       |        | ( |                |                           |
|      |       |        | I |                |                           |
|      |       |        | L |                |                           |
|      |       |        | G |                |                           |
|      |       |        | F |                |                           |
|      |       |        | - |                |                           |
|      |       |        | 1 |                |                           |
|      |       |        | ) |                |                           |
|      |       |        | l |                |                           |
|      |       |        | e |                |                           |
|      |       |        | v |                |                           |
|      |       |        | e |                |                           |
|      |       |        | l |                |                           |
|      |       |        | s |                |                           |
|      |       |        | , |                |                           |
|      |       |        | D |                |                           |
|      |       |        | - |                |                           |
|      |       |        | x |                |                           |
|      |       |        | y |                |                           |
|      |       |        | l |                |                           |
|      |       |        | o |                |                           |
|      |       |        | s |                |                           |
|      |       |        | e |                |                           |
|      |       |        | a |                |                           |
|      |       |        | b |                |                           |
|      |       |        | s |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | p |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        | , |                |                           |
|      |       |        | m |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | p |                |                           |
|      |       |        | h |                |                           |
|      |       |        | o |                |                           |
|      |       |        | l |                |                           |
|      |       |        | o |                |                           |
|      |       |        | g |                |                           |
|      |       |        | y |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        | D |                |                           |
|      |       |        | N |                |                           |
|      |       |        | A |                |                           |
|      |       |        | p |                |                           |
|      |       |        | r |                |                           |
|      |       |        | o |                |                           |
|      |       |        | l |                |                           |
|      |       |        | i |                |                           |
|      |       |        | f |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        | o |                |                           |
|      |       |        | f |                |                           |
|      |       |        | s |                |                           |
|      |       |        | m |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | l |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | m |                |                           |
|      |       |        | u |                |                           |
|      |       |        | c |                |                           |
|      |       |        | o |                |                           |
|      |       |        | s |                |                           |
|      |       |        | a |                |                           |
|      |       |        | , |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        | g |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | r |                |                           |
|      |       |        | o |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | t |                |                           |
|      |       |        | r |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | s |                |                           |
|      |       |        | i |                |                           |
|      |       |        | t |                |                           |
|      |       |        | w |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        | e |                |                           |
|      |       |        | v |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | u |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | T |                |                           |
|      |       |        | x |                |                           |
|      |       |        | s |                |                           |
|      |       |        | w |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        | c |                |                           |
|      |       |        | c |                |                           |
|      |       |        | o |                |                           |
|      |       |        | m |                |                           |
|      |       |        | p |                |                           |
|      |       |        | a |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | b |                |                           |
|      |       |        | y |                |                           |
|      |       |        | p |                |                           |
|      |       |        | a |                |                           |
|      |       |        | i |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | * |                |                           |
|      |       |        | t |                |                           |
|      |       |        | * |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | . |                |                           |
+------+-------+--------+---+----------------+---------------------------+
| S    |       |        |   |                |                           |
| cola |       |        |   |                |                           |
| pio, |       |        |   |                |                           |
| JS   |       |        |   |                |                           |
| et   |       |        |   |                |                           |
| al.  |       |        |   |                |                           |
| Ef   |       |        |   |                |                           |
| fect |       |        |   |                |                           |
| of   |       |        |   |                |                           |
| Gr   |       |        |   |                |                           |
| owth |       |        |   |                |                           |
| Horm |       |        |   |                |                           |
| one, |       |        |   |                |                           |
| Gl   |       |        |   |                |                           |
| utam |       |        |   |                |                           |
| ine, |       |        |   |                |                           |
| and  |       |        |   |                |                           |
| Diet |       |        |   |                |                           |
| on   |       |        |   |                |                           |
| Ad   |       |        |   |                |                           |
| apta |       |        |   |                |                           |
| tion |       |        |   |                |                           |
| in   |       |        |   |                |                           |
| Sho  |       |        |   |                |                           |
| rt - |       |        |   |                |                           |
| B    |       |        |   |                |                           |
| owel |       |        |   |                |                           |
| S    |       |        |   |                |                           |
| yndr |       |        |   |                |                           |
| ome: |       |        |   |                |                           |
| A    |       |        |   |                |                           |
| ran  |       |        |   |                |                           |
| domi |       |        |   |                |                           |
| zed, |       |        |   |                |                           |
| Co   |       |        |   |                |                           |
| ntro |       |        |   |                |                           |
| lled |       |        |   |                |                           |
| St   |       |        |   |                |                           |
| udy. |       |        |   |                |                           |
| Gast |       |        |   |                |                           |
| roen |       |        |   |                |                           |
| tero |       |        |   |                |                           |
| logy |       |        |   |                |                           |
| 113: |       |        |   |                |                           |
| 1    |       |        |   |                |                           |
| 074- |       |        |   |                |                           |
| 1081 |       |        |   |                |                           |
| (1   |       |        |   |                |                           |
| 997) |       |        |   |                |                           |
+------+-------+--------+---+----------------+---------------------------+
| **   | 8     | D      | - |                | -   In this study, the    |
| 7.** | pat   | ouble- |   |                |     combination high-dose |
|      | ients | blind, |   |                |     GH and glutamine      |
|      | (7w   | p      |   |                |     **did not**           |
|      | omen, | lacebo | B |                |     **increase body       |
|      | 1     | -contr | o |                |     weight, lean body     |
|      | man)  | olled, | d |                |     mass** (LBM), **fat   |
|      | with  | rando  | y |                |     mass** (FM) and       |
|      | SBS   | mized, |   |                |     **bone mass           |
|      | and   | cros   |   |                |     significantly         |
|      | **    | sover. |   |                |     compared to placebo   |
|      | intes |        |   |                |     treatment.**          |
|      | tinal | Active | w |                |                           |
|      | fa    | Tx     | e |                | -   However, body weight  |
|      | ilure | con    | i |                |     increased 1.03 kg     |
|      | depe  | sisted | g |                |     (1.7%, p \< 0.05),    |
|      | nding | of     | h |                |     LBM 2.93 kg (8.7%, p  |
|      | on    | subcut | t |                |     \< 0.001) and FM      |
|      | home  | aneous |   |                |     decreased 2.41 kg     |
|      | paren | **     |   |                |     (10.6%, p \< 0.001)   |
|      | teral | rhGH** |   |                |     in comparison with    |
|      | nutr  |        |   |                |     baseline.             |
|      | ition | **     | a |                |                           |
|      | for 3 | \[0.14 | n |                | -   24-h urine creatinine |
|      | to 11 | mg     | d |                |     excretion did not     |
|      | years | /kg/d; |   |                |     differ between study  |
|      | and   | Nordit |   |                |     periods.              |
|      | with  | ropin, |   |                |                           |
|      | 1 to  | Novo-N |   |                | -   No changes in         |
|      | 11    | ordisk | c |                |     intestinal absorption |
|      | years | AS,    | o |                |     of FAs were seen and  |
|      | to    | Bags   | m |                |     no changes in EFAs    |
|      | last  | vaerd, | p |                |     measured in plasma    |
|      | sur   | Den    | o |                |     phospholipids were    |
|      | gical | mark\] | s |                |     observed.             |
|      | proce | d      | i |                |                           |
|      | dure. | ivided | t |                | -   Only 1 of 8 patients, |
|      | Res   | into 2 | i |                |     who did not receive   |
|      | idual | daily  | o |                |     parenteral lipids,    |
|      | small | injec  | n |                |     had a Holman index    |
|      | bowel | tions, | , |                |     above 0.2, indicative |
|      | l     | oral   |   |                |     of EFA deficiency.    |
|      | ength | l-glu  |   |                |                           |
|      | was   | tamine |   |                | -   All patients          |
|      | 30 to | (30    |   |                |     developed peripheral  |
|      | 150   | g/d;   | m |                |     edema.                |
|      | cm**  | Ajin   | e |                |                           |
|      | and 4 | omoto, | a |                |                           |
|      | pat   | Ka     | s |                |                           |
|      | ients | wasaki | u |                |                           |
|      | had a | City,  | r |                |                           |
|      | part  | Japan) | e |                |                           |
|      | of    | d      | d |                |                           |
|      | colon | ivided |   |                |                           |
|      | in    | into 6 |   |                |                           |
|      | fun   | doses  |   |                |                           |
|      | ction | dis    |   |                |                           |
|      | (28%, | solved | b |                |                           |
|      | 43%,  | in a   | y |                |                           |
|      | 86%,  | be     |   |                |                           |
|      | and   | verage |   |                |                           |
|      | 86%). | of the |   |                |                           |
|      |       | pati   |   |                |                           |
|      |       | ents\' | d |                |                           |
|      |       | c      | u |                |                           |
|      |       | hoice, | a |                |                           |
|      |       | and    | l |                |                           |
|      |       | pare   |   |                |                           |
|      |       | nteral |   |                |                           |
|      |       | GLN as |   |                |                           |
|      |       | GLN-en |   |                |                           |
|      |       | riched | e |                |                           |
|      |       | inf    | n |                |                           |
|      |       | usions | e |                |                           |
|      |       | (17%   | r |                |                           |
|      |       | of N   | g |                |                           |
|      |       | as     | y |                |                           |
|      |       | GLN;   |   |                |                           |
|      |       | Gla    |   |                |                           |
|      |       | vamin, |   |                |                           |
|      |       | Pharm  |   |                |                           |
|      |       | acia-U | X |                |                           |
|      |       | pjohn, | - |                |                           |
|      |       | Sw     | r |                |                           |
|      |       | eden** | a |                |                           |
|      |       | **)    | y |                |                           |
|      |       | .**    |   |                |                           |
|      |       |        |   |                |                           |
|      |       | The    |   |                |                           |
|      |       | other  |   |                |                           |
|      |       | group  | a |                |                           |
|      |       | was    | b |                |                           |
|      |       | rand   | s |                |                           |
|      |       | omized | o |                |                           |
|      |       | to     | r |                |                           |
|      |       | p      | p |                |                           |
|      |       | lacebo | t |                |                           |
|      |       |        | i |                |                           |
|      |       | trea   | o |                |                           |
|      |       | tment. | m |                |                           |
|      |       |        | e |                |                           |
|      |       | Each   | t |                |                           |
|      |       | tre    | r |                |                           |
|      |       | atment | y |                |                           |
|      |       | period |   |                |                           |
|      |       | lasted |   |                |                           |
|      |       | 28     |   |                |                           |
|      |       | days.  |   |                |                           |
|      |       | At     | ( |                |                           |
|      |       | home,  | N |                |                           |
|      |       | pa     | o |                |                           |
|      |       | tients | r |                |                           |
|      |       | co     | d |                |                           |
|      |       | nsumed | l |                |                           |
|      |       | their  | a |                |                           |
|      |       | ha     | n |                |                           |
|      |       | bitual | d |                |                           |
|      |       | diets. |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | X |                |                           |
|      |       |        | R |                |                           |
|      |       |        | 3 |                |                           |
|      |       |        | 6 |                |                           |
|      |       |        | , |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | N |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | d |                |                           |
|      |       |        | l |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | C |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | p |                |                           |
|      |       |        | . |                |                           |
|      |       |        | , |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | W |                |                           |
|      |       |        | i |                |                           |
|      |       |        | s |                |                           |
|      |       |        | . |                |                           |
|      |       |        | , |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | U |                |                           |
|      |       |        | S |                |                           |
|      |       |        | A |                |                           |
|      |       |        | ) |                |                           |
|      |       |        |   |                |                           |
|      |       |        | - |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | U |                |                           |
|      |       |        | r |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | a |                |                           |
|      |       |        | r |                |                           |
|      |       |        | y |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | c |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | e |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | e |                |                           |
|      |       |        | x |                |                           |
|      |       |        | c |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | m |                |                           |
|      |       |        | e |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | u |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | 5 |                |                           |
|      |       |        | 0 |                |                           |
|      |       |        | 5 |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | n |                |                           |
|      |       |        | m |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | a |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | p |                |                           |
|      |       |        | i |                |                           |
|      |       |        | k |                |                           |
|      |       |        | r |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        | - |                |                           |
|      |       |        | c |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | e |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | c |                |                           |
|      |       |        | o |                |                           |
|      |       |        | m |                |                           |
|      |       |        | p |                |                           |
|      |       |        | l |                |                           |
|      |       |        | e |                |                           |
|      |       |        | x |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | u |                |                           |
|      |       |        | s |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | g |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | a |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        | a |                |                           |
|      |       |        | r |                |                           |
|      |       |        | d |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | H |                |                           |
|      |       |        | o |                |                           |
|      |       |        | s |                |                           |
|      |       |        | p |                |                           |
|      |       |        | i |                |                           |
|      |       |        | t |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | y |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | c |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | c |                |                           |
|      |       |        | h |                |                           |
|      |       |        | n |                |                           |
|      |       |        | i |                |                           |
|      |       |        | q |                |                           |
|      |       |        | u |                |                           |
|      |       |        | e |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | ( |                |                           |
|      |       |        | m |                |                           |
|      |       |        | e |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | o |                |                           |
|      |       |        | d |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | o |                |                           |
|      |       |        | f |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | J |                |                           |
|      |       |        | a |                |                           |
|      |       |        | f |                |                           |
|      |       |        | f |                |                           |
|      |       |        | e |                |                           |
|      |       |        | ) |                |                           |
|      |       |        | . |                |                           |
|      |       |        |   |                |                           |
|      |       |        | - |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | D |                |                           |
|      |       |        | i |                |                           |
|      |       |        | e |                |                           |
|      |       |        | t |                |                           |
|      |       |        | a |                |                           |
|      |       |        | r |                |                           |
|      |       |        | y |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | F |                |                           |
|      |       |        | e |                |                           |
|      |       |        | c |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | y |                |                           |
|      |       |        | s |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | . |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | T |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | d |                |                           |
|      |       |        | i |                |                           |
|      |       |        | e |                |                           |
|      |       |        | t |                |                           |
|      |       |        | a |                |                           |
|      |       |        | r |                |                           |
|      |       |        | y |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | f |                |                           |
|      |       |        | e |                |                           |
|      |       |        | c |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | F |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | w |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | d |                |                           |
|      |       |        | e |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | m |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | b |                |                           |
|      |       |        | y |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | c |                |                           |
|      |       |        | o |                |                           |
|      |       |        | m |                |                           |
|      |       |        | b |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | G |                |                           |
|      |       |        | L |                |                           |
|      |       |        | C |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | M |                |                           |
|      |       |        | S |                |                           |
|      |       |        | W |                |                           |
|      |       |        | . |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | I |                |                           |
|      |       |        | n |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | F |                |                           |
|      |       |        | A |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | a |                |                           |
|      |       |        | b |                |                           |
|      |       |        | s |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | p |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | w |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | c |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | c |                |                           |
|      |       |        | u |                |                           |
|      |       |        | l |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | d |                |                           |
|      |       |        | i |                |                           |
|      |       |        | f |                |                           |
|      |       |        | f |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        | n |                |                           |
|      |       |        | c |                |                           |
|      |       |        | e |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | b |                |                           |
|      |       |        | e |                |                           |
|      |       |        | t |                |                           |
|      |       |        | w |                |                           |
|      |       |        | e |                |                           |
|      |       |        | e |                |                           |
|      |       |        | n |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | g |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | e |                |                           |
|      |       |        | x |                |                           |
|      |       |        | c |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | F |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | . |                |                           |
|      |       |        |   |                |                           |
|      |       |        | - |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | F |                |                           |
|      |       |        | A |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | c |                |                           |
|      |       |        | o |                |                           |
|      |       |        | m |                |                           |
|      |       |        | p |                |                           |
|      |       |        | o |                |                           |
|      |       |        | s |                |                           |
|      |       |        | i |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | o |                |                           |
|      |       |        | f |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | p |                |                           |
|      |       |        | l |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | m |                |                           |
|      |       |        | a |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | p |                |                           |
|      |       |        | h |                |                           |
|      |       |        | o |                |                           |
|      |       |        | s |                |                           |
|      |       |        | p |                |                           |
|      |       |        | h |                |                           |
|      |       |        | o |                |                           |
|      |       |        | l |                |                           |
|      |       |        | i |                |                           |
|      |       |        | p |                |                           |
|      |       |        | i |                |                           |
|      |       |        | d |                |                           |
|      |       |        | s |                |                           |
|      |       |        | . |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | T |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | F |                |                           |
|      |       |        | A |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | m |                |                           |
|      |       |        | e |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | y |                |                           |
|      |       |        | l |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | s |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | w |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | y |                |                           |
|      |       |        | z |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | b |                |                           |
|      |       |        | y |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        |   |                |                           |
|      |       |        | G |                |                           |
|      |       |        | L |                |                           |
|      |       |        | C |                |                           |
|      |       |        | . |                |                           |
+------+-------+--------+---+----------------+---------------------------+
| Jepp |       |        |   |                |                           |
| esen |       |        |   |                |                           |
| PB.  |       |        |   |                |                           |
| Ef   |       |        |   |                |                           |
| fect |       |        |   |                |                           |
| of   |       |        |   |                |                           |
| H    |       |        |   |                |                           |
| igh- |       |        |   |                |                           |
| Dose |       |        |   |                |                           |
| gr   |       |        |   |                |                           |
| owth |       |        |   |                |                           |
| Hor  |       |        |   |                |                           |
| mone |       |        |   |                |                           |
| and  |       |        |   |                |                           |
| G    |       |        |   |                |                           |
| luta |       |        |   |                |                           |
| mine |       |        |   |                |                           |
| on   |       |        |   |                |                           |
| Body |       |        |   |                |                           |
| Comp |       |        |   |                |                           |
| osit |       |        |   |                |                           |
| ion, |       |        |   |                |                           |
| U    |       |        |   |                |                           |
| rine |       |        |   |                |                           |
| Cr   |       |        |   |                |                           |
| eati |       |        |   |                |                           |
| nine |       |        |   |                |                           |
| Ex   |       |        |   |                |                           |
| cret |       |        |   |                |                           |
| ion, |       |        |   |                |                           |
| F    |       |        |   |                |                           |
| atty |       |        |   |                |                           |
| Acid |       |        |   |                |                           |
| Ab   |       |        |   |                |                           |
| sorp |       |        |   |                |                           |
| tion |       |        |   |                |                           |
| and  |       |        |   |                |                           |
| E    |       |        |   |                |                           |
| ssen |       |        |   |                |                           |
| tial |       |        |   |                |                           |
| F    |       |        |   |                |                           |
| atty |       |        |   |                |                           |
| A    |       |        |   |                |                           |
| cids |       |        |   |                |                           |
| St   |       |        |   |                |                           |
| atus |       |        |   |                |                           |
| in   |       |        |   |                |                           |
| S    |       |        |   |                |                           |
| hort |       |        |   |                |                           |
| B    |       |        |   |                |                           |
| owel |       |        |   |                |                           |
| Pati |       |        |   |                |                           |
| ents |       |        |   |                |                           |
| Scan |       |        |   |                |                           |
| J    |       |        |   |                |                           |
| G    |       |        |   |                |                           |
| astr |       |        |   |                |                           |
| oent |       |        |   |                |                           |
| erol |       |        |   |                |                           |
| 36:4 |       |        |   |                |                           |
| 8-54 |       |        |   |                |                           |
| (2   |       |        |   |                |                           |
| 001) |       |        |   |                |                           |
+------+-------+--------+---+----------------+---------------------------+
| 8\.  | 61    | Open-  |   | Vitamin, trace | -   Of the 61 pts., 49    |
|      | s     | label, |   | elements       |     were dependent upon   |
|      | table | u      |   | levels, and    |     PN, infusing on       |
|      | adult | ncontr |   | liver and      |     average 6 +- 1 days   |
|      | pat   | olled. |   | kidney         |     per week, 2.2         |
|      | ients | All    |   | function were  |     [+]{.underline} 1 L   |
|      | with  | pts.   |   | assessed upon  |     per infusion, at the  |
|      | anato | a      |   | admission and  |     time of admission. Of |
|      | mical | dhered |   | then           |     these 49, 20 were     |
|      | SBS,  | to a   |   | reassessed at  |     weaned completely     |
|      | de    | standa |   | 6 and 12       |     from PN and remained  |
|      | fined | rdized |   | months after   |     off for an average of |
|      | as    | bowel  |   | discharge.     |     1 year following      |
|      | \<=   | re     |   |                |     admission to the      |
|      | 200   | habili |   | Throughout the |     in-home program; 25   |
|      | cm of | tation |   | entire         |     pts. experienced a    |
|      | re    | r      |   | in-house       |     reduction in PN       |
|      | mnant | egimen |   | period, body   |     requirements and 4    |
|      | small | thro   |   | weight and all |     had no change in PN.  |
|      | b     | ughout |   | parenteral and |                           |
|      | owel. | the    |   | enteral intake | -   19 of the 20 pts.     |
|      | The   | in     |   | and output of  |     weaned completely off |
|      | l     | -house |   | urine, stool   |     of PN, maintained     |
|      | ength | period |   | and emesis     |     their weight within   |
|      | of    | (4 to  |   | were recorded  |     10% of their          |
|      | time  | 6      |   | daily.         |     admission or ideal    |
|      | from  | weeks) |   |                |     body weight range; 8  |
|      | small | and    |   | Serum          |     of these were able to |
|      | bowel | were   |   | ele3ctrolytes  |     gain weight (2% to    |
|      | rese  | then   |   | were typically |     17% increase from     |
|      | ction | mon    |   | assessed one   |     admission weight) off |
|      | was 4 | itored |   | to two times   |     of PN, most notably,  |
|      | +- 5  | and    |   | per week.      |     3 pts. with jejunal   |
|      | y     | a      |   |                |     -ileal lengths of 12  |
|      | ears. | dhered |   | These same     |     to 17 cm anastomosed  |
|      | In    | to the |   | parameters     |     to a portion of       |
|      | add   | pres   |   | were monitored |     colon.                |
|      | ition | cribed |   | throughout the |                           |
|      | to    | r      |   | follow-up      | -   Of the 25 pts. who    |
|      | SBS,  | egimen |   | period with    |     experienced a         |
|      | 6     | thro   |   | the frequency  |     reduction in PN, 21   |
|      | pts.  | ughout |   | dependent upon |     maintained their      |
|      | also  | the    |   | the clinical   |     weight within 10% of  |
|      | had   | fol    |   | course of the  |     their admission or    |
|      | ch    | low-up |   | patient..      |     ideal body weight     |
|      | ronic | period |   |                |     range. **Despite an   |
|      | radi  | (6 and |   |                |     initial positive      |
|      | ation | 12     |   |                |     response to the bowel |
|      | enter | month  |   |                |     rehabilitation        |
|      | itis. | s).The |   |                |     regimen, 4 of these   |
|      | Of    | r      |   |                |     pts. lost greater     |
|      | the   | egimen |   |                |     than 10%of their      |
|      | 61    | con    |   |                |     weight.; 3 of these 4 |
|      | pts,  | sisted |   |                |     pts. were eventually  |
|      | 49    | of     |   |                |     referred for          |
|      | were  | medica |   |                |     intestinal            |
|      | depe  | tions, |   |                |     transplantation..**   |
|      | ndent | a      |   |                |                           |
|      | upon  | sp     |   |                | -   **The 4 pts. who      |
|      | PN at | ecific |   |                |     experienced no change |
|      | the   | diet   |   |                |     in their PN           |
|      | time  | with   |   |                |     requirements          |
|      | of    | supple |   |                |     following a           |
|      | admi  | ments, |   |                |     standardized bowl     |
|      | ssion | and a  |   |                |     rehabilitation        |
|      | and   | be     |   |                |     regimen were also     |
|      | 12    | havior |   |                |     referred for          |
|      | were  | modifi |   |                |     intestinal            |
|      | ref   | cation |   |                |     transplantation..**   |
|      | erred | pro    |   |                |                           |
|      | with  | gram.. |   |                | -   The complications     |
|      | the   |        |   |                |     associated with the   |
|      | i     | **GH   |   |                |     bowel rehabilitation  |
|      | ntent | \[     |   |                |     regimen included :    |
|      | of    | Serono |   |                |                           |
|      | preve | L      |   |                | (1) mild fluid retention, |
|      | nting | aborat |   |                |     which occurred in the |
|      | the   | ories, |   |                |     majority of the       |
|      | initi | No     |   |                |     patients . and was    |
|      | ation | rwell, |   |                |     attributed to the     |
|      | or    | MA and |   |                |     administration of GH, |
|      | r     | Eli    |   |                |     and treated, if       |
|      | e3sum | Lilly, |   |                |     indicated, with a     |
|      | ption | I      |   |                |     diuretic, and         |
|      | of    | ndiana |   |                |                           |
|      | this  | polis, |   |                | (2) an increase in gas    |
|      | mode  | IND    |   |                |     and bloating, related |
|      | of    | USA\]  |   |                |     to the changes in the |
|      | sup   | was    |   |                |     diet, particularly    |
|      | port. | given  |   |                |     the CHO content.      |
|      |       | at the |   |                |                           |
|      |       | dose   |   |                |                           |
|      |       | of     |   |                |                           |
|      |       | 0.09   |   |                |                           |
|      |       | mg     |   |                |                           |
|      |       | /kg/d. |   |                |                           |
|      |       | Oral   |   |                |                           |
|      |       | GLN    |   |                |                           |
|      |       | \[Cam  |   |                |                           |
|      |       | bridge |   |                |                           |
|      |       | Nut    |   |                |                           |
|      |       | raceut |   |                |                           |
|      |       | icals, |   |                |                           |
|      |       | B      |   |                |                           |
|      |       | oston, |   |                |                           |
|      |       | Mass,  |   |                |                           |
|      |       | USA\]  |   |                |                           |
|      |       | was    |   |                |                           |
|      |       | pr     |   |                |                           |
|      |       | ovided |   |                |                           |
|      |       | at a   |   |                |                           |
|      |       | dose** |   |                |                           |
|      |       |        |   |                |                           |
|      |       | **30 g |   |                |                           |
|      |       | /d (5  |   |                |                           |
|      |       | g/ 6x  |   |                |                           |
|      |       | per    |   |                |                           |
|      |       | day)** |   |                |                           |
+------+-------+--------+---+----------------+---------------------------+
| B    |       |        |   |                |                           |
| yrne |       |        |   |                |                           |
| TA   |       |        |   |                |                           |
| et   |       |        |   |                |                           |
| al.  |       |        |   |                |                           |
| B    |       |        |   |                |                           |
| owel |       |        |   |                |                           |
| reh  |       |        |   |                |                           |
| abil |       |        |   |                |                           |
| itat |       |        |   |                |                           |
| ion: |       |        |   |                |                           |
| an   |       |        |   |                |                           |
| alt  |       |        |   |                |                           |
| erna |       |        |   |                |                           |
| tive |       |        |   |                |                           |
| to   |       |        |   |                |                           |
| l    |       |        |   |                |                           |
| ong- |       |        |   |                |                           |
| term |       |        |   |                |                           |
| pa   |       |        |   |                |                           |
| rent |       |        |   |                |                           |
| eral |       |        |   |                |                           |
| n    |       |        |   |                |                           |
| utri |       |        |   |                |                           |
| tion |       |        |   |                |                           |
| and  |       |        |   |                |                           |
| in   |       |        |   |                |                           |
| test |       |        |   |                |                           |
| inal |       |        |   |                |                           |
| tra  |       |        |   |                |                           |
| nspl |       |        |   |                |                           |
| anta |       |        |   |                |                           |
| tion |       |        |   |                |                           |
| for  |       |        |   |                |                           |
| some |       |        |   |                |                           |
| pati |       |        |   |                |                           |
| ents |       |        |   |                |                           |
| with |       |        |   |                |                           |
| s    |       |        |   |                |                           |
| hort |       |        |   |                |                           |
| b    |       |        |   |                |                           |
| owel |       |        |   |                |                           |
| s    |       |        |   |                |                           |
| yndr |       |        |   |                |                           |
| ome. |       |        |   |                |                           |
| Tr   |       |        |   |                |                           |
| ansp |       |        |   |                |                           |
| Proc |       |        |   |                |                           |
| 34:  |       |        |   |                |                           |
| 887  |       |        |   |                |                           |
| -890 |       |        |   |                |                           |
| (2   |       |        |   |                |                           |
| 002) |       |        |   |                |                           |
+------+-------+--------+---+----------------+---------------------------+
| **   | 12    | Prosp  | I |                | -   **Treatment with GH   |
| 9.** | pat   | ective | m |                |     increased intestinal  |
|      | ients | rando  | m |                |     absorption of         |
|      | from  | mized, | e |                |     energy** (15%         |
|      | the   | d      | d |                |     [+]{.underline} 5%, p |
|      | reg   | ouble- | i |                |     \< 0.002),            |
|      | ister | blind, | a |                |     **nitrogen** (14%     |
|      | of    | p      | t |                |     [+]{.underline} 6%, p |
|      | HPN   | lacebo | e |                |     \< ).04), CHOs (10%   |
|      | -depe | -contr | l |                |     [+]{.underline} 4%, p |
|      | ndent | olled, | y |                |     \< 0.04), **and fat** |
|      | pat   | cros   | b |                |     (12% [+]{.underline}  |
|      | ients | sover. | e |                |     8%, NS).              |
|      | with  | All    | f |                |                           |
|      | SBS.  | pts.   | o |                | ```{=html}                |
|      | All   | were   | r |                | <!-- -->                  |
|      | had   | on an  | e |                | ```                       |
|      | unde  | unrest | t |                | -   According to the      |
|      | rgone | ricted | h |                |     authors\'             |
|      | exte  | hyper  | e |                |     calculations, the     |
|      | nsive | phagic | f |                |     increased food        |
|      | rese  | diet.. | i |                |     absorption            |
|      | ction |        | r |                |     represented 37% + 16% |
|      | of    | **Pa   | s |                |     of total parenteral   |
|      | the   | tients | t |                |     energy delivery.      |
|      | small | re     | T |                |                           |
|      | bowel | ceived | x |                | ```{=html}                |
|      | wi    | d      | p |                | <!-- -->                  |
|      | thout | aily** | e |                | ```                       |
|      | any   | **lo   | r |                | -   **Body weight** (p \< |
|      | sur   | w-dose | i |                |     0.003), **lean body   |
|      | gical | GH \[  | o |                |     mass** (p \< 0.006),  |
|      | rese  | 0.05   | d |                |     **D-xylose**          |
|      | ction | mg .   | ( |                |     **absorption** (p \<  |
|      | of    | kg     | b |                |     0.02), **insulin-like |
|      | the   | ^-1^ . | a |                |     growth factor 1** (p  |
|      | sto   | d      | s |                |     \< 0.002), and        |
|      | mach, | ay^-1^ | e |                |     **insulin-like growth |
|      | duo   | \] ,   | l |                |     factor binding        |
|      | denum | c      | i |                |     protein 3** (p \<     |
|      | or    | orresp | n |                |     0.002) **increased,** |
|      | panc  | onding | e |                |     whereas uptake of GH  |
|      | reas. | to**   | ) |                |     binding protein       |
|      |       |        | a |                |     decreased (p \< 0.01) |
|      | Usual | **0.15 | n |                |     , without any         |
|      | m     | IU kg  | d |                |     apparent major        |
|      | edica | ^-1^./ | a |                |     adverse effect.       |
|      | tions | day^-  | t |                |                           |
|      | such  | 1\ \]^ | t |                |                           |
|      | as    | \      | h |                |                           |
|      | PPIs, | [Genot | e |                |                           |
|      | l     | ropin, | c |                |                           |
|      | opera | Pha    | o |                |                           |
|      | mide, | rmacia | n |                |                           |
|      | fl    | and    | c |                |                           |
|      | uoroq | Upjohn | l |                |                           |
|      | uinol | AB,    | u |                |                           |
|      | ones, | Stoc   | s |                |                           |
|      | and   | kholm, | i |                |                           |
|      | oral  | Sw     | o |                |                           |
|      | s     | eden\] | n |                |                           |
|      | upple | admini | o |                |                           |
|      | ments | stered | f |                |                           |
|      | vi    | by     | e |                |                           |
|      | tamin | subcut | a |                |                           |
|      | E, D, | aneous | c |                |                           |
|      | Ca,   | inj    | h |                |                           |
|      | K, Mg | ection | T |                |                           |
|      | s     | daily  | x |                |                           |
|      | alts) | at     | p |                |                           |
|      | were  | 8am.** | e |                |                           |
|      | not   |        | r |                |                           |
|      | ch    |        | i |                |                           |
|      | anged |        | o |                |                           |
|      | d     |        | d |                |                           |
|      | uring |        | d |                |                           |
|      | the   |        | a |                |                           |
|      | s     |        | y |                |                           |
|      | tudy. |        | 2 |                |                           |
|      |       |        | 1 |                |                           |
|      |       |        | ) |                |                           |
|      |       |        | , |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | u |                |                           |
|      |       |        | t |                |                           |
|      |       |        | r |                |                           |
|      |       |        | i |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        | u |                |                           |
|      |       |        | s |                |                           |
|      |       |        | ( |                |                           |
|      |       |        | b |                |                           |
|      |       |        | o |                |                           |
|      |       |        | d |                |                           |
|      |       |        | y |                |                           |
|      |       |        | w |                |                           |
|      |       |        | e |                |                           |
|      |       |        | i |                |                           |
|      |       |        | g |                |                           |
|      |       |        | h |                |                           |
|      |       |        | t |                |                           |
|      |       |        | , |                |                           |
|      |       |        | b |                |                           |
|      |       |        | o |                |                           |
|      |       |        | d |                |                           |
|      |       |        | y |                |                           |
|      |       |        | m |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | s |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        | e |                |                           |
|      |       |        | x |                |                           |
|      |       |        | , |                |                           |
|      |       |        | s |                |                           |
|      |       |        | k |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | f |                |                           |
|      |       |        | o |                |                           |
|      |       |        | l |                |                           |
|      |       |        | d |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | i |                |                           |
|      |       |        | c |                |                           |
|      |       |        | k |                |                           |
|      |       |        | n |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | s |                |                           |
|      |       |        | , |                |                           |
|      |       |        | b |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | e |                |                           |
|      |       |        | l |                |                           |
|      |       |        | e |                |                           |
|      |       |        | c |                |                           |
|      |       |        | t |                |                           |
|      |       |        | r |                |                           |
|      |       |        | i |                |                           |
|      |       |        | c |                |                           |
|      |       |        | i |                |                           |
|      |       |        | m |                |                           |
|      |       |        | p |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | c |                |                           |
|      |       |        | e |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | y |                |                           |
|      |       |        | s |                |                           |
|      |       |        | i |                |                           |
|      |       |        | s |                |                           |
|      |       |        | ) |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | s |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | s |                |                           |
|      |       |        | m |                |                           |
|      |       |        | e |                |                           |
|      |       |        | n |                |                           |
|      |       |        | t |                |                           |
|      |       |        | w |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | p |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | f |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | m |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | . |                |                           |
|      |       |        |   |                |                           |
|      |       |        | A |                |                           |
|      |       |        | t |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | a |                |                           |
|      |       |        | m |                |                           |
|      |       |        | e |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | m |                |                           |
|      |       |        | e |                |                           |
|      |       |        | , |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | i |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | o |                |                           |
|      |       |        | f |                |                           |
|      |       |        | b |                |                           |
|      |       |        | l |                |                           |
|      |       |        | o |                |                           |
|      |       |        | o |                |                           |
|      |       |        | d |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | s |                |                           |
|      |       |        | , |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | c |                |                           |
|      |       |        | l |                |                           |
|      |       |        | u |                |                           |
|      |       |        | d |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | g |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        | m |                |                           |
|      |       |        | o |                |                           |
|      |       |        | g |                |                           |
|      |       |        | r |                |                           |
|      |       |        | a |                |                           |
|      |       |        | m |                |                           |
|      |       |        | , |                |                           |
|      |       |        | g |                |                           |
|      |       |        | l |                |                           |
|      |       |        | u |                |                           |
|      |       |        | c |                |                           |
|      |       |        | o |                |                           |
|      |       |        | s |                |                           |
|      |       |        | e |                |                           |
|      |       |        | , |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | s |                |                           |
|      |       |        | u |                |                           |
|      |       |        | l |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | , |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | s |                |                           |
|      |       |        | u |                |                           |
|      |       |        | l |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | - |                |                           |
|      |       |        | l |                |                           |
|      |       |        | i |                |                           |
|      |       |        | k |                |                           |
|      |       |        | e |                |                           |
|      |       |        | g |                |                           |
|      |       |        | r |                |                           |
|      |       |        | o |                |                           |
|      |       |        | w |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | f |                |                           |
|      |       |        | a |                |                           |
|      |       |        | c |                |                           |
|      |       |        | t |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | 1 |                |                           |
|      |       |        | ( |                |                           |
|      |       |        | I |                |                           |
|      |       |        | G |                |                           |
|      |       |        | F |                |                           |
|      |       |        | - |                |                           |
|      |       |        | 1 |                |                           |
|      |       |        | ) |                |                           |
|      |       |        | , |                |                           |
|      |       |        | I |                |                           |
|      |       |        | G |                |                           |
|      |       |        | F |                |                           |
|      |       |        | b |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | g |                |                           |
|      |       |        | p |                |                           |
|      |       |        | r |                |                           |
|      |       |        | o |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | 3 |                |                           |
|      |       |        | ( |                |                           |
|      |       |        | I |                |                           |
|      |       |        | G |                |                           |
|      |       |        | F |                |                           |
|      |       |        | B |                |                           |
|      |       |        | P |                |                           |
|      |       |        | - |                |                           |
|      |       |        | 3 |                |                           |
|      |       |        | ) |                |                           |
|      |       |        | , |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        | G |                |                           |
|      |       |        | H |                |                           |
|      |       |        | b |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | g |                |                           |
|      |       |        | p |                |                           |
|      |       |        | r |                |                           |
|      |       |        | o |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        |   |                |                           |
|      |       |        | ( |                |                           |
|      |       |        | G |                |                           |
|      |       |        | H |                |                           |
|      |       |        | B |                |                           |
|      |       |        | P |                |                           |
|      |       |        | , |                |                           |
|      |       |        | s |                |                           |
|      |       |        | o |                |                           |
|      |       |        | l |                |                           |
|      |       |        | u |                |                           |
|      |       |        | b |                |                           |
|      |       |        | l |                |                           |
|      |       |        | e |                |                           |
|      |       |        | f |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | m |                |                           |
|      |       |        | o |                |                           |
|      |       |        | f |                |                           |
|      |       |        | G |                |                           |
|      |       |        | H |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        | c |                |                           |
|      |       |        | e |                |                           |
|      |       |        | p |                |                           |
|      |       |        | t |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | ) |                |                           |
|      |       |        | s |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | u |                |                           |
|      |       |        | m |                |                           |
|      |       |        | l |                |                           |
|      |       |        | e |                |                           |
|      |       |        | v |                |                           |
|      |       |        | e |                |                           |
|      |       |        | l |                |                           |
|      |       |        | s |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | w |                |                           |
|      |       |        | e |                |                           |
|      |       |        | l |                |                           |
|      |       |        | l |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | p |                |                           |
|      |       |        | l |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | m |                |                           |
|      |       |        | a |                |                           |
|      |       |        | g |                |                           |
|      |       |        | l |                |                           |
|      |       |        | u |                |                           |
|      |       |        | t |                |                           |
|      |       |        | a |                |                           |
|      |       |        | m |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | e |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        | c |                |                           |
|      |       |        | i |                |                           |
|      |       |        | t |                |                           |
|      |       |        | r |                |                           |
|      |       |        | u |                |                           |
|      |       |        | l |                |                           |
|      |       |        | l |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | e |                |                           |
|      |       |        | a |                |                           |
|      |       |        | m |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | o |                |                           |
|      |       |        | a |                |                           |
|      |       |        | c |                |                           |
|      |       |        | i |                |                           |
|      |       |        | d |                |                           |
|      |       |        | l |                |                           |
|      |       |        | e |                |                           |
|      |       |        | v |                |                           |
|      |       |        | e |                |                           |
|      |       |        | l |                |                           |
|      |       |        | s |                |                           |
|      |       |        | , |                |                           |
|      |       |        | w |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | p |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | f |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | m |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        | b |                |                           |
|      |       |        | l |                |                           |
|      |       |        | o |                |                           |
|      |       |        | o |                |                           |
|      |       |        | d |                |                           |
|      |       |        | s |                |                           |
|      |       |        | a |                |                           |
|      |       |        | m |                |                           |
|      |       |        | p |                |                           |
|      |       |        | l |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | a |                |                           |
|      |       |        | k |                |                           |
|      |       |        | e |                |                           |
|      |       |        | n |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | a |                |                           |
|      |       |        | p |                |                           |
|      |       |        | o |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | a |                |                           |
|      |       |        | b |                |                           |
|      |       |        | s |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | p |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | v |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | ( |                |                           |
|      |       |        | 7 |                |                           |
|      |       |        | a |                |                           |
|      |       |        | m |                |                           |
|      |       |        | ) |                |                           |
|      |       |        | . |                |                           |
|      |       |        |   |                |                           |
|      |       |        | D |                |                           |
|      |       |        | u |                |                           |
|      |       |        | r |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | g |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | i |                |                           |
|      |       |        | r |                |                           |
|      |       |        | d |                |                           |
|      |       |        | w |                |                           |
|      |       |        | e |                |                           |
|      |       |        | e |                |                           |
|      |       |        | k |                |                           |
|      |       |        | o |                |                           |
|      |       |        | f |                |                           |
|      |       |        | e |                |                           |
|      |       |        | a |                |                           |
|      |       |        | c |                |                           |
|      |       |        | h |                |                           |
|      |       |        | T |                |                           |
|      |       |        | x |                |                           |
|      |       |        | p |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | d |                |                           |
|      |       |        | , |                |                           |
|      |       |        | p |                |                           |
|      |       |        | t |                |                           |
|      |       |        | s |                |                           |
|      |       |        | . |                |                           |
|      |       |        | w |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        | a |                |                           |
|      |       |        | d |                |                           |
|      |       |        | m |                |                           |
|      |       |        | i |                |                           |
|      |       |        | t |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | f |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | 5 |                |                           |
|      |       |        | d |                |                           |
|      |       |        | a |                |                           |
|      |       |        | y |                |                           |
|      |       |        | s |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        | 4 |                |                           |
|      |       |        | n |                |                           |
|      |       |        | i |                |                           |
|      |       |        | g |                |                           |
|      |       |        | h |                |                           |
|      |       |        | t |                |                           |
|      |       |        | s |                |                           |
|      |       |        | ( |                |                           |
|      |       |        | d |                |                           |
|      |       |        | a |                |                           |
|      |       |        | y |                |                           |
|      |       |        | s |                |                           |
|      |       |        | 1 |                |                           |
|      |       |        | 7 |                |                           |
|      |       |        | t |                |                           |
|      |       |        | o |                |                           |
|      |       |        | 2 |                |                           |
|      |       |        | 1 |                |                           |
|      |       |        | ) |                |                           |
|      |       |        | t |                |                           |
|      |       |        | o |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | u |                |                           |
|      |       |        | d |                |                           |
|      |       |        | y |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | m |                |                           |
|      |       |        | a |                |                           |
|      |       |        | c |                |                           |
|      |       |        | r |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        | u |                |                           |
|      |       |        | t |                |                           |
|      |       |        | r |                |                           |
|      |       |        | i |                |                           |
|      |       |        | e |                |                           |
|      |       |        | n |                |                           |
|      |       |        | t |                |                           |
|      |       |        | a |                |                           |
|      |       |        | b |                |                           |
|      |       |        | s |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | p |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        | * |                |                           |
|      |       |        | * |                |                           |
|      |       |        | ( |                |                           |
|      |       |        | m |                |                           |
|      |       |        | a |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | j |                |                           |
|      |       |        | u |                |                           |
|      |       |        | d |                |                           |
|      |       |        | g |                |                           |
|      |       |        | m |                |                           |
|      |       |        | e |                |                           |
|      |       |        | n |                |                           |
|      |       |        | t |                |                           |
|      |       |        | c |                |                           |
|      |       |        | r |                |                           |
|      |       |        | i |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | i |                |                           |
|      |       |        | a |                |                           |
|      |       |        | ) |                |                           |
|      |       |        | . |                |                           |
|      |       |        | * |                |                           |
|      |       |        | * |                |                           |
|      |       |        |   |                |                           |
|      |       |        | * |                |                           |
|      |       |        | * |                |                           |
|      |       |        | D |                |                           |
|      |       |        | u |                |                           |
|      |       |        | r |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | g |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        | f |                |                           |
|      |       |        | i |                |                           |
|      |       |        | r |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | d |                |                           |
|      |       |        | a |                |                           |
|      |       |        | y |                |                           |
|      |       |        | o |                |                           |
|      |       |        | f |                |                           |
|      |       |        | h |                |                           |
|      |       |        | o |                |                           |
|      |       |        | s |                |                           |
|      |       |        | p |                |                           |
|      |       |        | i |                |                           |
|      |       |        | t |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | i |                |                           |
|      |       |        | z |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        | ( |                |                           |
|      |       |        | d |                |                           |
|      |       |        | a |                |                           |
|      |       |        | y |                |                           |
|      |       |        | 1 |                |                           |
|      |       |        | 7 |                |                           |
|      |       |        | ) |                |                           |
|      |       |        | , |                |                           |
|      |       |        | a |                |                           |
|      |       |        | D |                |                           |
|      |       |        | - |                |                           |
|      |       |        | x |                |                           |
|      |       |        | y |                |                           |
|      |       |        | l |                |                           |
|      |       |        | o |                |                           |
|      |       |        | s |                |                           |
|      |       |        | e |                |                           |
|      |       |        | a |                |                           |
|      |       |        | b |                |                           |
|      |       |        | s |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | p |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | w |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | p |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | f |                |                           |
|      |       |        | o |                |                           |
|      |       |        | r |                |                           |
|      |       |        | m |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | . |                |                           |
|      |       |        | T |                |                           |
|      |       |        | h |                |                           |
|      |       |        | u |                |                           |
|      |       |        | s |                |                           |
|      |       |        | , |                |                           |
|      |       |        | a |                |                           |
|      |       |        | m |                |                           |
|      |       |        | i |                |                           |
|      |       |        | n |                |                           |
|      |       |        | i |                |                           |
|      |       |        | m |                |                           |
|      |       |        | u |                |                           |
|      |       |        | m |                |                           |
|      |       |        | 2 |                |                           |
|      |       |        | 3 |                |                           |
|      |       |        | - |                |                           |
|      |       |        | d |                |                           |
|      |       |        | a |                |                           |
|      |       |        | y |                |                           |
|      |       |        | w |                |                           |
|      |       |        | a |                |                           |
|      |       |        | s |                |                           |
|      |       |        | h |                |                           |
|      |       |        | o |                |                           |
|      |       |        | u |                |                           |
|      |       |        | t |                |                           |
|      |       |        | p |                |                           |
|      |       |        | e |                |                           |
|      |       |        | r |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | d |                |                           |
|      |       |        | a |                |                           |
|      |       |        | c |                |                           |
|      |       |        | t |                |                           |
|      |       |        | u |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | l |                |                           |
|      |       |        | y |                |                           |
|      |       |        | e |                |                           |
|      |       |        | l |                |                           |
|      |       |        | a |                |                           |
|      |       |        | p |                |                           |
|      |       |        | s |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | b |                |                           |
|      |       |        | e |                |                           |
|      |       |        | t |                |                           |
|      |       |        | w |                |                           |
|      |       |        | e |                |                           |
|      |       |        | e |                |                           |
|      |       |        | n |                |                           |
|      |       |        | t |                |                           |
|      |       |        | h |                |                           |
|      |       |        | e |                |                           |
|      |       |        | e |                |                           |
|      |       |        | v |                |                           |
|      |       |        | a |                |                           |
|      |       |        | l |                |                           |
|      |       |        | u |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        | o |                |                           |
|      |       |        | f |                |                           |
|      |       |        | t |                |                           |
|      |       |        | e |                |                           |
|      |       |        | s |                |                           |
|      |       |        | t |                |                           |
|      |       |        | m |                |                           |
|      |       |        | e |                |                           |
|      |       |        | d |                |                           |
|      |       |        | i |                |                           |
|      |       |        | c |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        | i |                |                           |
|      |       |        | o |                |                           |
|      |       |        | n |                |                           |
|      |       |        | a |                |                           |
|      |       |        | n |                |                           |
|      |       |        | d |                |                           |
|      |       |        | p |                |                           |
|      |       |        | l |                |                           |
|      |       |        | a |                |                           |
|      |       |        | c |                |                           |
|      |       |        | e |                |                           |
|      |       |        | b |                |                           |
|      |       |        | o |                |                           |
|      |       |        | t |                |                           |
|      |       |        | r |                |                           |
|      |       |        | e |                |                           |
|      |       |        | a |                |                           |
|      |       |        | t |                |                           |
|      |       |        | m |                |                           |
|      |       |        | e |                |                           |
|      |       |        | n |                |                           |
|      |       |        | t |                |                           |
|      |       |        | s |                |                           |
|      |       |        | . |                |                           |
|      |       |        | * |                |                           |
|      |       |        | * |                |                           |
+------+-------+--------+---+----------------+---------------------------+
| S    |       |        |   |                |                           |
| eguy |       |        |   |                |                           |
| d et |       |        |   |                |                           |
| al.  |       |        |   |                |                           |
| Low- |       |        |   |                |                           |
| Dose |       |        |   |                |                           |
| Gr   |       |        |   |                |                           |
| owth |       |        |   |                |                           |
| Hor  |       |        |   |                |                           |
| mone |       |        |   |                |                           |
| in   |       |        |   |                |                           |
| A    |       |        |   |                |                           |
| dult |       |        |   |                |                           |
| Home |       |        |   |                |                           |
| Pa   |       |        |   |                |                           |
| rent |       |        |   |                |                           |
| eral |       |        |   |                |                           |
| Nut  |       |        |   |                |                           |
| riti |       |        |   |                |                           |
| on-D |       |        |   |                |                           |
| epen |       |        |   |                |                           |
| dent |       |        |   |                |                           |
| S    |       |        |   |                |                           |
| hort |       |        |   |                |                           |
| B    |       |        |   |                |                           |
| owel |       |        |   |                |                           |
| Synd |       |        |   |                |                           |
| rome |       |        |   |                |                           |
| P    |       |        |   |                |                           |
| atie |       |        |   |                |                           |
| nts: |       |        |   |                |                           |
| A    |       |        |   |                |                           |
| Posi |       |        |   |                |                           |
| tive |       |        |   |                |                           |
| St   |       |        |   |                |                           |
| udy. |       |        |   |                |                           |
| Gast |       |        |   |                |                           |
| roen |       |        |   |                |                           |
| tero |       |        |   |                |                           |
| logy |       |        |   |                |                           |
| 124: |       |        |   |                |                           |
| 293  |       |        |   |                |                           |
| -302 |       |        |   |                |                           |
| (2   |       |        |   |                |                           |
| 003) |       |        |   |                |                           |
+------+-------+--------+---+----------------+---------------------------+

C.  []{#__RefHeading___Toc514120897 .anchor}**Were Trials Conducted in
    Accordance with Accepted Ethical Standards**

> Yes.

### E. Evaluation of Financial Disclosure

> Adequate Financial documentation was submitted for the following
> Investigators/Sub-investigators participating in pivotal Protocol No.
> IMP20317,
>
> \"Randomized, Double-blind, Controlled, Parallel-Group Evaluation of
> the Relative Efficacy and Safety of Recombinant Human growth Hormone
> and Glutamine, Singly and as Co-therapy, in the Improvement of
> Residual Gut Absorptive Function in Patients with Short Bowel
> Syndrome\":
>
> David B. Lautz, MD \[Brigham and Women\'s Hospital, Boston, MA\],
> David Clark Jacobsen, MD \[Harvard Vangard Medical Associates,
> Medford, MA\], Theresa Byrne, D.Sc., R.D., Nutrition Restart Center,
> Hopkinton, MA\], Malcolm K. Robinson, MD \[Brigham and Women\'s
> Hospital, Boston, MA\], Kishore R. Iyer, MBBS, FRCS, University of
> Nebraska Medical Center, Omaha, NE\] and John K. DiBaise, MD,
> University of Nebraska medical Center, Omaha, NE\].

**In this reviewer\'s opinion, none of these financial disclosures could
cast doubt on the findings presented by the sponsor of this NDA.**

## VI. Integrated Review of Efficacy 

### A. Brief Statement of Conclusions

> As noted in Section I.A. of the current review, the sponsor is seeking
> the indication \"*treatment of SBS in patients receiving specialized
> nutritional support. Serostim^®^ therapy should be used in conjunction
> with optimal management of SBS\".* In support of this request, the
> sponsor evaluated the effects of the drug in SBS patients who were
> dependent on intravenous parenteral nutrition for nutritional support.
> This assessment showed a decrease in the Total IPN volume requirement
> (therapeutic gain = 3.9 liters per week) in SBS patients who were
> receiving a specialized diet and were given rh-GH, at the
> subcutaneously administered daily dose of 0.1mg/kg plus glutamine, in
> comparison to a control. The latter consisted of SBS patients who, in
> addition to the specialized diet (as the experimental group) were
> given glutamine and rh-GH placebo.
>
> However, as noted in several sections of the current review, issues
> such as the clinical validity of the protocol-stipulated primary
> efficacy parameter, the effect of low-dose of the hormone,
> replicability/generalizability, the potential toxicity of GH when
> administered long-term and the role of glutamine and the \"specialized
> diet\" need to be carefully considered before definitive conclusions
> can be formulated.

### B. General Approach to Review of the Efficacy of the Drug

The efficacy database consists primarily of results from pivotal
Protocol No. IMP20317, a (one) randomized clinical trial undertaken to
evaluate the \"relative\" efficacy and safety of rh-GH and glutamine,
singly and as co-therapy, in the **improvement of residual gut
absorptive function in patients with short bowel syndrome.**

This study was reviewed in detail.

In addition, although the sponsor has not submitted any additional data
as supportive, the reviewer elected to assess and summarize information
published in the literature that is pertinent to the application (Table
2) to address certain issues. These issues include proof of principle
(**does GH have an effect -in any way or** **fashion- in the treatment
of SBS patients**?). Emphasis was put on publications, if any, that
tested the sponsor\'s formulation of the hormone.

### Detailed Review of Trials by Indication

> The sponsor submitted results of a single trial, for a single, new
> indication. This trial is entitled \"***Randomized, Double-Blind,
> Controlled, Parallel-Group Evaluation of the Relative Efficacy of
> Recombinant Human growth Hormone and Glutamine, Singly and as
> Cotherapy, in the Improvement of Residual Gut Absorptive Function in
> Patients with Short Bowel Syndrome\".*** The Clinical Study Report
> (Protocol No. IMP20317) is reviewed in detail below.

-   The study was initiated on 23 July 1998 and completed on 27 June
    2002.

-   There were two Principal Investigators : a) David Lautz, MD
    \[Brigham and Women\'s Hospital, Boston MA\], with three
    Sub-investigators and Nutritional Restart Center, Wellesley, MA as
    the study site and b) Kishore R. Iyer, M.B., B.S., F.R.C.S.
    \[University of Nebraska, Omaha, NE\] with one sub-investigator and
    the University of Nebraska as the study site.

-   The primary objective of the study was to evaluate the change in
    intravenous parenteral nutrition (IPN) requirements measured during
    Week 2 (last week of baseline period) to that seen at Week 6 (last
    week of Treatment Period) in adult, IPN-dependent, SBS subjects
    receiving a specialized oral diet (SOD) supplemented with glutamine
    (GLN), Serostim^®^ recombinant human growth hormone (rh-GH) with a
    SOD, or rh-GH with a SOD supplemented with GLN.

```{=html}
<!-- -->
```
-   The overall study design was that of a randomized, double-blind,
    placebo-controlled, parallel-group, 3-arm, Phase III clinical trial.

-   After screening and following completion of a 2-week Baseline Period
    , the Treatment Period consisted of 4 weeks, after which subjects
    were discharged on a SOD supplemented with either GLN or GLN
    Placebo; subjects were reevaluated as outpatients 12 weeks later.

-   The study population consisted of 41 randomized patients (age range
    : 20 to 75 y; age categories : \< 65y, n = 33; \>= 65y, n = 8; 32
    Caucasian, 9 Non-Caucasian; 29 females and 12 males). The study
    population (Table 3) was adequate for this type of study.

> **Table 3**

**Study IMP20317**

**Characteristics of the Study population**

+-----------------------------------+-----------------------------------+
| **INCLUSION CRITERIA**            | **REASONS FOR EXCLUSION**         |
+-----------------------------------+-----------------------------------+
| -   M or F, between 18 and 75y of | -   Body mass index grater than   |
|     age                           |     28                            |
+-----------------------------------+-----------------------------------+
| -   Diagnosis of SBS with less    | -   Pregnancy or lactation        |
|     than or equal to 200 cm small |                                   |
|     bowel                         | -   Ongoing, chronic infectious   |
|                                   |     disease                       |
+-----------------------------------+-----------------------------------+
| -   Eat at least some solid food  | -   History of cancer within 5y   |
|     on a regular basis, but       |     of entry into the Baseline    |
|     require at least 3000 cal.    |     Period (non-melanoma skin     |
|     per week of IPN for           |     cancer or in situ carcinoma   |
|     nutritional support           |     of the cervix are not reasons |
|                                   |     for exclusion)                |
+-----------------------------------+-----------------------------------+
| -   Have:                         | -   History of mental deficiency  |
|                                   |     or illness that might         |
| ```{=html}                        |     compromise with the           |
| <!-- -->                          |     requirements of the study.    |
| ```                               |     History of psychiatric eating |
| -   body mass index equal to or   |     disorder or drug or alcohol   |
|     greater than 17               |     abuse are reasons for         |
|                                   |     exclusion                     |
| -   undergone bowel resection     |                                   |
|     surgery at least 6 mo. prior  | -   Sustained hypertension        |
|     to entering the trial and     |     (arterial pressure of \>=     |
|     have an intact stomach and    |     160/100 mm Hg or more on 2    |
|     duodenum and one or more of   |     successive measurements)      |
|     the following:                |                                   |
|                                   | -   Secretory bowel disease, as   |
| a)  at least 30% of the colon     |     demonstrated by a stool       |
|     remaining functional and at   |     output of greater than or     |
|     least 15 cm of jejunum or     |     equal to 800 mL per 24-h      |
|     ileum remaining intact        |     period when there has been no |
|                                   |     oral intake of food for 24h   |
| b)  less than 30% of the colon    |                                   |
|     remaining functional but      | -   Clinically serious            |
|     having at least 90 cm of      |     neurological disfunction      |
|     jejunum or ileum remaining    |                                   |
|     intact                        | -   Established diagnosis of      |
|                                   |     diabetes mellitus             |
| c)  less than or equal to 3L per  |                                   |
|     day of stool output           | -   Hypoxemic pulmonary disease   |
|                                   |     (i.e. resting pAO~2~ \<= 75   |
| d)  an acceptable level of liver  |     torr)                         |
|     function, with a total serum  |                                   |
|     bilirubin concentration less  | -   Unstable ischemic heart       |
|     than 3 times the upper limit  |     disease or uncompensated      |
|     of normal, and renal          |     cardiac failure               |
|     function, with a serum        |                                   |
|     creatinine concentration less | -   Any condition requiring       |
|     than or equal to              |     either daily systemic         |
|                                   |     glucocorticoids exceeding a   |
| 3 mg/dL                           |     dose equivalent to 10 mg/d    |
|                                   |     prednisone or significant     |
| e)  the ability to understand the |     immunosuppressant therapy     |
|     requirements of the study, to |     (e.g. active inflammatory     |
|     provide written informed      |     bowel disease,                |
|     consent and to abide by the   |     collagen-vascular disease,    |
|     study restrictions and agree  |     autoimmune disorder, or       |
|     to complete the required      |     radiation enteritis)          |
|     assessment in the follow-up   |                                   |
|     period.                       | -   History of carpal tunnel      |
|                                   |     syndrome unless surgical      |
|                                   |     release has been performed    |
|                                   |                                   |
|                                   | -   Participation in any study    |
|                                   |     involving investigational     |
|                                   |     drugs within 30 days prior to |
|                                   |     entry into this trial         |
|                                   |                                   |
|                                   | -   Have received rhGH or any     |
|                                   |     other type of growth factor   |
|                                   |     that may affect intestinal    |
|                                   |     absorption                    |
+-----------------------------------+-----------------------------------+
| -   For women participating in    |                                   |
|     this trial, manifest or give  |                                   |
|     assent to adequate criteria   |                                   |
|     to ensure that the patient    |                                   |
|     does not become pregnant      |                                   |
|     during the trial              |                                   |
+-----------------------------------+-----------------------------------+
| -   For pts. with known           |                                   |
|     hypertension or other         |                                   |
|     cardiovascular disorder, be   |                                   |
|     both compensated and          |                                   |
|     stabilized on a regular       |                                   |
|     therapeutic regimen           |                                   |
+-----------------------------------+-----------------------------------+

-   The methods/procedures/approaches to remove patients from therapy
    were adequate.

-   **DOSE SELECTION/TIMING OF DOSING**

> The sponsor states that the dosage of rhGH chosen for this study was
> based upon previous experience in SBS patients. Doses ranging from
> 0.07 to 0.14 mg/kg/d have been shown to be effective in decreasing
> IPN-dependence in SBS patients (publications by T. A. Byrne, D.W.
> Wilmore). A dose of 0.10 mg/kg/d was selected because of its \"good
> safety and efficacy profile\" . The GLN supplementation was selected
> on the basis of past experience in SBS patients and suggestions from
> the Agency during the pre-IND meeting on 19 October 1994.
>
> Each patient was scheduled to receive a daily subcutaneous injection
> of **0.10 mg/kg rh-GH** or **rh-GH placebo** (to a maximum dose of 8
> mg/d) for 4 weeks, calculated using a step-wise dosing procedure
> depending on patient\'s weight (ranging from 4 mg/d for a patient
> whose weight was 35 to 44.9 kg to 8 mg kg/d for a \>=75 kg patient.
>
> Each patient received a daily oral supplement of GLN (30 g /d) or GLN
> placebo (27 g/d) divided into 6 single dose packets that were each
> mixed with water or Crystal Light beverage according to the patient\'s
> preference. Patients consumed the beverages with meals or snacks at
> 2-to3 -h intervals during the day. The volume of the beverage could be
> varied according to the patient\'s tolerance.[^32]
>
> **NOTE:** All study participants received an oral diet individualized
> to meet nutritional needs. It is important to note that modifications
> to the diet throughout the treatment period were necessary to maintain
> adequate nutrition status. As noted by Dr. D. Price, the FDA
> Statistician reviewer, due to changes to the diet after randomization
> and the potentially complex relationship between diet and total IPN
> volume, an unbiased statistical analysis adjusting for the diet effect
> is not possible. However, data on the diet and nutritional status of
> patients serve to provide clinicians with a descriptive clarification
> of the nature and strength of the relationship between diet and IPN
> utilization over time. Additional pertinent information on the diet is
> included in Section X of the current review.

-   **RANDOMIZATION/BLINDING**

```{=html}
<!-- -->
```
-   The randomization scheme and codes were submitted in sponsor\'s
    Appendix 16.1.7 (volume 1, page 263 through 266). The proposed
    randomization scheme was appropriate The plan called for random
    assignment of subjects in a 2:2:1 ratio at each site to one of the 3
    treatment arms (*i.e.,* Group A, rhGH + SOD; Group B, rhGH +
    SOD\[GLN\]; and Group C, rhGH placebo + SOD\[GLN\]. The block size
    was 5.

```{=html}
<!-- -->
```
-   The randomization process was properly executed. Subjects were
    randomly assigned using PROC PLAN.[^33] Patient randomization codes
    were maintained in sealed envelopes in the medical monitor\'s locked
    file.[^34]

```{=html}
<!-- -->
```
-   The study qualifies as being double-blinded. The methods to conceal
    the identity of the test medication from participating physicians
    and patients were all adequate. The injectable clinical trial
    material (CTM), rh-GH or rh-GH placebo, was identical in appearance
    and packaging.[^35] The oral supplement (GLN or GLN placebo) was
    identical in volume, appearance, and packaging.[^36]

```{=html}
<!-- -->
```
-   **PRIOR AND CONCOMITANT THERAPY/COMPLIANCE**

> The procedures to handle prior and concomitant medications, especially
> those that may be potentially confounding, were all adequate. Equally
> adequate were the procedures to determine treatment compliance.

-   **PRIMARY EFFICACY PARAMETER**

> **The primary efficacy parameter** was the change from Week 2 to Week
> 6 in the total volume of IPN required by each patient for nutritional
> support. The sponsor states that following discussion with the DMEDP,
> **IPN volume was selected to achieve an accurate analysis of efficacy
> since it is less variable than IPN calories.**
>
> **NOTE:** An important issue that needs to be addressed is whether
> **changes in IPN volume** per week \--rather than **measurements of
> adequate parameters to assess clinical/biochemical/nutritional
> status\--** is a valid/important/relevant primary efficacy parameter
> to determine efficacy of the drug in the SBS indication that the
> sponsor is requesting.
>
> This issue, which is a pivotal determinant when assessing
> approvability of the drug for the sought indication, is discussed in
> many sections of the current review. This issue is also the subject of
> Advisory Committee discussions. The current review continues on the
> certainly debatable assumption that change in IPN volume is a
> valid/relevant/clinically important primary efficacy parameter.
>
> **Definition of Total IPN volume**

-   Total volume is the sum of the volumes of:

> a\) IPN volume plus

b.  b\) supplemental lipid emulsion (SLE) plus

c\) intravenous hydration fluid administered each week.

-   IPN and SLE requirements were captured on a daily basis during Week
    2 through 6.

-   **SECONDARY EFFICACY PARAMETERS**

> There were two (2) secondary parameters of efficacy:
>
> 1\) **Mean change in Total IPN calories (calories per week) from Week
> 2 to 6.**
>
> Total calories are defined as the sum of kilocalories for CHO,
> protein, and fat in the IPN.
>
> 2\) **Mean change in IPN or SLE frequency(days per week) from Week 2
> to 6.**
>
> **Frequency** is defined as the number of days per week of
> administration of IPN or, if no IPN, administration of SLE where the
> amount of SLE provides greater than 200 kcal.[^37]
>
> In addition, the sponsor attempted to evaluate the persistence of
> observed treatment effects. To accomplish this, the change in weekly
> volume of IPN used during Week 2 versus Week 6 was compared with the
> change in weekly volume requirements during Week 6 versus Week 18
> (last week of the Follow-up Period).[^38]
>
> Furthermore, the sponsor analyzed other related efficacy parameters in
> an attempt to examine the consistency of effects over time. This was
> done through a repeated-measures analysis of all primary, secondary,
> and other efficacy parameters. Such an analysis used all the data from
> Week 2 through Week 6. In addition, **hydration fluid intake, urine
> output, and stool output for all treatment groups for Week 2 and Week
> 6 were compared.** Because such an evaluation may provide some
> evidence of fluid balance, the reviewer elected to examine data for
> the last three parameters.
>
> **TEST MEDICATION**
>
> **This was recombinant human growth hormone (Serostim®); subcutaneous
> injection at a dose of 0.10 mg/kg/d.**[^39]
>
> Also made use of was rh-GH placebo; subcutaneous injection; 0.10
> mg/kg/d.[^40]
>
> **DURATION OF TREATMENT**
>
> **GROUP A:** rh-GH + SOD for 4 weeks followed by SOD for 12 weeks.
>
> **GROUP B**: rh-GH + SOD \[GLN\] for 4 weeks followed by SOD \[GLN\]
> for 12 weeks.
>
> **GROUP C**: rh-GH placebo + SOD\[GLN\] for 4 weeks followed by
> SOD\[GLN\] for 12 weeks.
>
> **CRITERIA FOR EVALUATION OF SAFETY**
>
> The procedures to gather, process, analyze and report trial emerging
> adverse events, whether clinical or laboratory abnormalities, were all
> adequate.
>
> **STATISTICS**
>
> **Determination of Sample Size**
>
> The sample size calculation was based on the number of patients (i.e.
> 17) studied by Byrne[^41].
>
> Patients in the Byrne study received rh-GH + SOD \[GLN\] and were
> evaluated within 6 months of the end of treatment. Based on this
> experience, a total of 40 patients \[Group A, n = 16, Group B,
>
> n = 16, and Group C, n = 8\] was needed to yield 80% power for the
> overall F test (α = 0.05) from a one-way ANOVA. This determination was
> made on the following assumptions:

-   That the difference in the decrease of IPN volume between Group B
    (rhGH + SOD \[GLN\]) and Group C, the control (rh-GH placebo + SOD
    \[GLN\] is **6.6 L per week** and

-   That the decrease in IPN volume between Group A (rh-GH + SOD\] and
    Group C (rh-GH placebo + SOD \[GLN) is **6.6 L per week and**

-   That the pooled root mean squared error is **5.5 L per week.**

**NOTE:** According to the Clinical Report, the original plan was to
enroll 5 additional patients to ensure that at least 40 patients
completed the trial.

The Clinical report states that analysis of covariance of the change in
total volume from Week 2 to Week 6, with Week 2 as the covariate and
with the treatment effect was used to compare the primary efficacy
parameter for the treatment arms. This statistical approach is
acceptable.

The secondary efficacy parameters were evaluated through pair-wise
comparisons of the least squares means of the two rhGH groups, Group A:
rhGH + SOD; Group B : rhGH + SOD \[GLN\] to the GLN-supplemented diet
group (Group C: rhGH placebo + SOD \[GLN\] by using the Dunnett-Hsu
t-test.

**Effects of Covariates**

Statistical models of the effects of other covariates on the primary and
secondary parameters were also assessed. Covariates that were assessed
include, but were not necessarily limited to: age, sex, race, weight
(this included weight history), time since diagnosis of SBS, time since
last resection (\< 12 months or \>= 12 months), length of residual
jejunum-ileum, presence of an intact colon, and IPN history (this
included weekly IPN volume, calories, and frequency).[^42]

The Clinical Report states that site effects were included in the above
models if multiple sites were used and the site effect was statistically
significant in the corresponding analysis excluding the covariate.
Covariates were assessed individually.[^43]

The safety analyses were conducted using the safety population. The
latter was defined as 41 patients randomized in the trial who had
postbaseline assessments. If all randomized patients had at least one
postbaseline assessment, then the safety population is identical to the
ITT population \[n = 41\].[^44]

**RESULTS**

**Disposition of Subjects**

-   Of the 47 patients considered for study participation, 6
    discontinued before randomization

> \[5 due to intercurrent illness and 1 because the patient withdrew
> informed consent\].

-   Of the 41 patients who entered the study, 38 were randomized at Site
    01, the other three at Site 02, with the distribution summarized in
    Table 4.

**Table 4**

**Study IMP20317**

**Summary of Patient Accrual**

**Number of Patients Randomized per Site and Treatment Arm**

+-------------+-------------+------------------+-------------+-------+
| **SITE**    | **GROUP A** | **GROUP B**      | **GROUP C** | **To  |
|             |             |                  |             | tal** |
|             | **(RhGH +   | **(rhGH + SOD    | **(SOD      |       |
|             | SOD)**      | \[GLN\])**       | \[GLN\])**  |       |
+-------------+-------------+------------------+-------------+-------+
| **01**      | **15**      | **15**           | **8**       | *     |
|             |             |                  |             | *38** |
+-------------+-------------+------------------+-------------+-------+
| **02**      | **1**       | **1**            | **1**       | **3** |
+-------------+-------------+------------------+-------------+-------+
| *           | **16^a^**   | **16**           | **9**       | *     |
| *Subtotal** |             |                  |             | *41** |
+-------------+-------------+------------------+-------------+-------+

a)  One patient (No. 106) was randomized to Group A on 26 October 1998
    and discontinued from the trial on 15 November 1998 (Week 5) due to
    a central line infection that resulted in fungemia. The number of
    patients completing the Treatment Period, as well as the Follow-Up
    Period was 15, 16, and 9, for Groups A, B, and C, respectively.

> **NOTE:** From the information summarized in Table 4, it is hard to
> characterize Study IMP20317 as being **multicenter.** This is because
> of the fact that the bulk of the patients in this study were
> randomized at one site (Site 01) while the other (Site 02) randomized
> one single patient per arm thereby contributing non-significantly to
> the data used to assess efficacy and safety of the drug in SBS
> patients.

**Protocol Deviations**

The Clinical Report included two Appendices, 16.2.1.1 and 16.2.1.2
listing all patient termination data, organized by site and treatment
group, including patient identifier, specific reasons for
discontinuation, and the date of discontinuation or termination. It is
explained that at the time of discontinuation, the blind was not broken
for any subject. The main protocol deviations by treatment arm for the
ITT study population, were summarized in sponsor\'s Table 10-1 (page
103) of the Clinical Report. Most of the protocol deviations consisted
of reduced dose of oral CTM for 1 to 7 days, followed by incomplete
vital sign assessments, missed 1 to 4 days of subcutaneous CTM
administration and missed incomplete vital sign assessments. There were
no gross imbalances among the 3 treatment arms regarding the protocol
deviations.

**Data Sets Analyzed**

There were 3 data sets analyzed : a) ITT (n = 41), defined as all
subjects that were randomized in the trial; b) Efficacy Evaluable (n =
40), defined as subjects that completed treatment period assessment
(i.e., IPN requirement assessments for 5 of 7 days during Week 2 and
Week 6), received at least 80% of scheduled CTM (i.e., 23 doses of
subcutaneous CTM and 135 doses of oral supplementation) and those who
did not have any protocol violations with a clinical impact; and c)
treatment responders. Because the reviewer feels this is an important
parameter of efficacy, the definition of treatment responder is given
below.

**Treatment Responder Population**

This study population includes all subjects who demonstrated a complete
response (i.e., **a 100% reduction in total IPN volume**) at Week 6.
Unfortunately, results in this study population were summarized
descriptively because each treatment group was not represented by at
least 2 subjects.

**SUBJECTS BASELINE CHARACTERISTICS**

All in all, the 3 treatment groups were comparable in terms of
demographic , disease and other baseline characteristics.

-   The treatment groups were comparable (no statistically significant
    differences among treatment arms) in demographic characteristics. As
    summarized in sponsor\'s Table 11-1 of the Clinical Report, the mean
    age for Groups A, B, and C was 50.5, 52.5, and 45.0 years,
    respectively. Roughly, two thirds of the patients were women, mostly
    Caucasian (there was a lower proportion of patients of non-Caucasian
    origin; although this difference approached statistical significance
    (p = 0.064) this imbalance is not expected to influence results.
    Similarly, the treatment arms were similar in baseline weight (Group
    A = 61.4 kg, Group B = 62.1 kg, and Group C = 61.3 kg). Weight was
    the average of each patient\'s weight at 1 month and 2 months before
    screening.

-   The underlying conditions resulting in bowel resection represented
    in all 3 treatment arms were vascular insufficiency, Crohn\'s
    disease, and volvulus. Other categories included patients with
    strangulated hernia, jejunoileal bypass for morbid obesity and
    other. There were no gross imbalances among the treatment arms in
    underlying condition resulting in bowel resection and the number of
    subjects per group was not sufficient for statistical analysis.

-   Similarly, at baseline, there was no statistically significant
    difference among the 3 treatment groups with regards to SBS and IPN
    history (Table 5). Results of evaluations regarding the 6
    SBS/IPN-related listed in this Table were carefully analyzed because
    parameters such as **mean length of residual jejunum-ileum , percent
    of colon intact , mean number of days per week of IPN
    administration, mean volume IPN per week, and mean IPN calories per
    week** are factors that may influence outcome.

**Table 5**

**Study IMP20317**

**Summary of Disease Baseline Characteristics**

+-------------------------+----------+--------------+---------+------+
| **SBS/IPN Variable**    | **Group  | **Group B    | **Group | **p  |
|                         | A        | rhGH+        | C       | -val |
|                         | rh       | SOD\[GLN\]** | SOD\[   | ue** |
|                         | GH+SOD** |              | GLN\]** |      |
|                         |          | **n = 16**   |         |      |
|                         | **n =    |              | **n =   |      |
|                         | 16**     |              | 9**     |      |
+-------------------------+----------+--------------+---------+------+
| **Mean number of years  | **5.1**  | **4.6**      | **3.9** | **N. |
| since most recent bowel |          |              |         | S.** |
| resection**             |          |              |         |      |
+-------------------------+----------+--------------+---------+------+
| **Mean length of        | **84.2** | **68.4**     | *       | **N. |
| residual jejunum-ileum  |          |              | *62.3** | S.** |
| \[cm\]**                |          |              |         |      |
+-------------------------+----------+--------------+---------+------+
| **Percent of Colon      | **67.1** | **52.6**     | *       | **N. |
| Intact**                |          |              | *61.8** | S.** |
+-------------------------+----------+--------------+---------+------+
| **Mean number of days   | **5.2**  | **5.5**      | **5.9** | **N. |
| per week of IPN         |          |              |         | S.** |
| administration**        |          |              |         |      |
+-------------------------+----------+--------------+---------+------+
| **Mean volume IPN per   | **       | **1852.2**   | **1     | **N. |
| week**                  | 1970.6** |              | 877.8** | S.** |
|                         |          |              |         |      |
| **\[mL/wk\]**           |          |              |         |      |
+-------------------------+----------+--------------+---------+------+
| **Mean IPN calories per | **       | **1486.3**   | **1     | **N. |
| week**                  | 1580.4** |              | 460.7** | S.** |
|                         |          |              |         |      |
| **\[kcal/wk\]**         |          |              |         |      |
+-------------------------+----------+--------------+---------+------+

This Table is based on sponsor\'s Tables 1.5.1 and 1.6.1 (Section 15.1)
and Summary Table 11-3 (page 108) of the Clinical Report. Standard
deviations have been omitted for clarity of presentation purposes.

> **RESULTS OF EFFICACY EVALUATIONS**
>
> **1. Groups Being Compared**

-   There were 3 arms in the trial. **The test medication arm is B**,
    which consists of rh-GH, SOD, and GLN (3 co-therapies).

-   **Arm C**, consisting of two co-therapies, SOD and GLN (like arm B)
    but containing no rh-GH, is a suitable control to test the effect of
    growth hormone (rh-GH) alone. For this comparison to be valid, there
    must be no significant changes between these two arms (B and C) in
    SOD as well as GLN.

-   Another comparison of interest might be that of B (3 co-therapies)
    **to A**, a test arm consisting of 2 co-therapies, rh-GH and SOD,
    but containing no GLN. Again, if SOD is common (in effects or lack
    of effects) to both arms, then this comparison B vs. A, may provide
    an assessment of the effect of glutamine alone.

> In summary, **the question of efficacy of growth hormone (alone) is
> settled by comparing** **results of Group B to C**. The question of
> **glutamine\'s contribution** might be settled by comparing results of
> **Group B to A**. This comparison, included in the reviewer\'s
> efficacy Tables, was carried by Dr. Dionne Price, FDA statistician. In
> their summary Tables of efficacy, the sponsor also included a
> comparison between Groups A and C. Assuming that SOD is common to both
> arms, this comparison is of little if any interest because it would
> test the effect of 2 variables: rhGH (in arm A) vs. GLN (in arm C). If
> carried out (as the sponsor has) this represents an active-active
> comparator situation but, owing to the small number of observations
> per cell, neither superiority nor non-inferiority hypotheses can be
> appropriately tested. Therefore, this comparison, A vs. C, is not
> assessed in detail in the reviewer\'s efficacy evaluations and it is
> only briefly commented upon within the text of this review.
>
> **2. Evaluations of Primary Efficacy Parameter (Table 6)**[^45]

-   For both, the ITT (upper panel of Table 6) and the EE population
    (lower panel of Table 6), a significant reduction in the Total IPN
    volume requirement was noted in patients who received rh-GH +
    SOD\[GLN\] (Group B) in comparison to the control, that is , those
    who received SOD + \[GLN\] (Group C). The therapeutic gain was 3.9
    L/wk. Whether a reduction in Total IPN volume requirement of 3.9
    L/wk is clinically meaningful, is a matter of debate. An
    unquestionably meaningful clinical nutrition endpoint would be the
    proportion of patients that, as the result of the intervention
    (administration of rh-GH + SOD\[GLN\]) **go off TPN and better yet,
    remain off TPN long-term.**

-   The other comparison of interest is that of Group B vs. Group A.
    This was carried out by the FDA statistician, Dr. D. Price. In her
    Statistical Review of NDA 21-597, Dr. Price notes that ascertainment
    of the relationship between rhGH alone versus rhGH in co-therapy
    with glutamine may provide some insight into the effect of the amino
    acid. Since , regardless of the study population evaluated, the
    difference between the comparison arms was not statistically
    significant, Dr. Price concluded that **glutamine has little or no
    effect.** This reviewer agrees that, under the conditions of these
    experiments, little if any glutamine contribution has been
    demonstrated. A decrease of less than 2 liters of Total IPN volume
    does not seem to be clinically important.

-   Although the comparison of A to C yielded a therapeutic gain of
    -**2.1 L/wk** and this difference was statistically significant in
    ITT Study Population evaluations, these results were not confirmed
    in analyses of the E-E Study Population (therapeutic gain = **-2.0
    L/wk**, p-value = N.S.). The reviewer believes that no firm
    conclusions may be drawn from such a comparison.

> **3. Evaluations of Secondary Efficacy Parameters (Table 7)**
>
> In the Clinical Report, the sponsor presented results of evaluations
> of 2 secondary efficacy parameters, the mean change in total IPN
> calories and the mean change in IPN or SLE Frequency from Week 2 to
> Week 6, for both secondary evaluation parameters.

**Table 6**

**Study IMP20317**

**Primary Efficacy Evaluation: Mean Change in Total IPN Volume \[L/wk\]
from Week 2 to Week 6**

+----------+----------------+-----------+----------+------------------+
| **T      |                |           | **The    |                  |
| reatment |                |           | rapeutic |                  |
| Groups** |                |           | gain**   |                  |
|          |                |           |          |                  |
|          |                |           | **\[L/w  |                  |
|          |                |           | k\]//(p- |                  |
|          |                |           | value)** |                  |
+----------+----------------+-----------+----------+------------------+
| **A**    | **B**          | **C**     | **B**    | **B A**          |
|          |                |           |          |                  |
| **rhGH + | **rhGH +       | **SOD     | **vs**   | **vs vs**        |
| SOD**    | SOD\[GLN\]**   | \[GLN\]** |          |                  |
|          |                |           | **C**    | **A C**          |
+----------+----------------+-----------+----------+------------------+
| **I. ITT |                |           |          |                  |
| STUDY    |                |           |          |                  |
| POPU     |                |           |          |                  |
| LATION** |                |           |          |                  |
+----------+----------------+-----------+----------+------------------+
| **\[n =  | **\[n = 16\]** | **\[n=    |          |                  |
| 16\]**   |                | 9\]**     |          |                  |
+----------+----------------+-----------+----------+------------------+
| **-5.9** | **-7.7**       | **-3.8**  | **-3.9** | **-1.8 -2.1**    |
|          |                |           |          |                  |
|          |                |           | **       | **\[N.S.\]^b^    |
|          |                |           | \[\<0.00 | \[0.043\]^c^**   |
|          |                |           | 1\]^a^** |                  |
+----------+----------------+-----------+----------+------------------+
| **II.    |                |           |          |                  |
| EF       |                |           |          |                  |
| FICACY-E |                |           |          |                  |
| VALUABLE |                |           |          |                  |
| STUDY    |                |           |          |                  |
| POPU     |                |           |          |                  |
| LATION** |                |           |          |                  |
+----------+----------------+-----------+----------+------------------+
| **\[n =  |                |           |          |                  |
| 15\] \[n |                |           |          |                  |
| = 16\]   |                |           |          |                  |
| \[n =    |                |           |          |                  |
| 9\]**    |                |           |          |                  |
+----------+----------------+-----------+----------+------------------+
| **-5.8** | **-7.7**       | **-3.8**  | **-3.9** | **-1.9 2.0**     |
|          |                |           |          |                  |
|          |                |           | **       | **\[N.S.\]^b^    |
|          |                |           | \[\<0.00 | \[N.S.\]^c^**    |
|          |                |           | 1\]^a^** |                  |
+----------+----------------+-----------+----------+------------------+
| This     |                |           |          |                  |
| Table is |                |           |          |                  |
| based on |                |           |          |                  |
| s        |                |           |          |                  |
| ponsor's |                |           |          |                  |
| Tables   |                |           |          |                  |
| 2.5.1.,  |                |           |          |                  |
| 2.9.1.1, |                |           |          |                  |
| 2.13.1   |                |           |          |                  |
| and      |                |           |          |                  |
| 2.5.2,   |                |           |          |                  |
| 2.9.2,   |                |           |          |                  |
| and      |                |           |          |                  |
| 2.13.2   |                |           |          |                  |
| and      |                |           |          |                  |
| Summary  |                |           |          |                  |
| Table    |                |           |          |                  |
| 11-4 and |                |           |          |                  |
| 11-7 of  |                |           |          |                  |
| the      |                |           |          |                  |
| Clinical |                |           |          |                  |
| Report.  |                |           |          |                  |
| Standard |                |           |          |                  |
| de       |                |           |          |                  |
| viations |                |           |          |                  |
| have     |                |           |          |                  |
| been     |                |           |          |                  |
| omitted  |                |           |          |                  |
| for      |                |           |          |                  |
| clarity  |                |           |          |                  |
| of       |                |           |          |                  |
| pres     |                |           |          |                  |
| entation |                |           |          |                  |
| p        |                |           |          |                  |
| urposes. |                |           |          |                  |
|          |                |           |          |                  |
| a,c)     |                |           |          |                  |
| These    |                |           |          |                  |
| p-values |                |           |          |                  |
| were     |                |           |          |                  |
| de       |                |           |          |                  |
| termined |                |           |          |                  |
| from     |                |           |          |                  |
| pairwise |                |           |          |                  |
| com      |                |           |          |                  |
| parisons |                |           |          |                  |
| of       |                |           |          |                  |
| t        |                |           |          |                  |
| reatment |                |           |          |                  |
| groups B |                |           |          |                  |
| and A    |                |           |          |                  |
| vs. the  |                |           |          |                  |
| "        |                |           |          |                  |
| control" |                |           |          |                  |
| (Group   |                |           |          |                  |
| C) by    |                |           |          |                  |
| Dun      |                |           |          |                  |
| nett-Hsu |                |           |          |                  |
| t-test   |                |           |          |                  |
| f        |                |           |          |                  |
| ollowing |                |           |          |                  |
| ANCOVA   |                |           |          |                  |
| with     |                |           |          |                  |
| Week 2   |                |           |          |                  |
| as       |                |           |          |                  |
| c        |                |           |          |                  |
| ovariate |                |           |          |                  |
| i        |                |           |          |                  |
| ncluding |                |           |          |                  |
| baseline |                |           |          |                  |
| by       |                |           |          |                  |
| t        |                |           |          |                  |
| reatment |                |           |          |                  |
| inte     |                |           |          |                  |
| raction. |                |           |          |                  |
|          |                |           |          |                  |
| b)To     |                |           |          |                  |
| extend   |                |           |          |                  |
| com      |                |           |          |                  |
| parisons |                |           |          |                  |
| to       |                |           |          |                  |
| include  |                |           |          |                  |
| all      |                |           |          |                  |
| pairwise |                |           |          |                  |
| comp     |                |           |          |                  |
| arisons, |                |           |          |                  |
| the FDA  |                |           |          |                  |
| stati    |                |           |          |                  |
| stician, |                |           |          |                  |
| Dr. D.   |                |           |          |                  |
| Price    |                |           |          |                  |
| applied  |                |           |          |                  |
| a        |                |           |          |                  |
| Tuke     |                |           |          |                  |
| y-Kramer |                |           |          |                  |
| test for |                |           |          |                  |
| this     |                |           |          |                  |
| com      |                |           |          |                  |
| parison. |                |           |          |                  |
|          |                |           |          |                  |
| NOTE: In |                |           |          |                  |
| the E-E  |                |           |          |                  |
| Study    |                |           |          |                  |
| Pop      |                |           |          |                  |
| ulation, |                |           |          |                  |
| the      |                |           |          |                  |
| number   |                |           |          |                  |
| of       |                |           |          |                  |
| patients |                |           |          |                  |
| is 15    |                |           |          |                  |
| because  |                |           |          |                  |
| results  |                |           |          |                  |
| of       |                |           |          |                  |
| Patient  |                |           |          |                  |
| No. 106  |                |           |          |                  |
| are not  |                |           |          |                  |
| i        |                |           |          |                  |
| ncluded. |                |           |          |                  |
+----------+----------------+-----------+----------+------------------+

> Table 7 displays data from evaluations in the ITT population only,
> because results from evaluations using the E-E Study population were
> nearly identical to those using the ITT analysis and therefore confirm
> the conclusions drawn from the latter analyses. As shown in Table 7,
> after 4 Weeks of treatment, subjects who received rh-GH + SOD\[GLN\]
> (Group B, the test medication arm) significantly reduced their Total
> IPN calorie content (therapeutic gain = -3117.9 kcal/wk) and their
> weekly frequency of IPN administration (therapeutic gain = -2.2 d/wk)
> in comparison to the control (Group C, subjects receiving SOD\[GLN\]
> without rh-GH). The results with secondary parameters of efficacy,
> reduction of 3,117.9 kcal/wk, and especially, a reduction by 2 out of
> 7 days per week in the need for Total IPN do not seem to be clinically
> impressive. It is important to note that neither the primary nor the
> secondary parameters of efficacy measures the patient's nutritional
> status. In an approach similar to that for the primary efficacy
> parameters where additional statistical evaluations by Dr. Price are
> included in Table 6, results of further statistical evaluation for the
> secondary efficacy endpoints are included in Table 7.
>
> Although, according to the sponsor's statistical analyses, the
> difference between Groups A and C are statistically significant for
> the secondary parameters of assessment, the clinical impact, a
> reduction of 1705.0 kcal per week, but specially, one day less (6
> instead of 7) in Total IPN or SLE, are of questionable clinical
> relevance.

**Table 7**

**Study IMP20317**

**Secondary Efficacy Evaluations**

**ITT STUDY POPULATION**

+----------+---------------+----------+---------+---------+---------+
| **T      |               |          | **Ther  |         |         |
| reatment |               |          | apeutic |         |         |
| Groups** |               |          | gain    |         |         |
|          |               |          | //(p-v  |         |         |
|          |               |          | alue)** |         |         |
+----------+---------------+----------+---------+---------+---------+
| **A**    | **B**         | **C**    | **B**   | **B**   | **A**   |
|          |               |          |         |         |         |
| **rhGH   | **rhGH        | **SOD\   | **vs**  | **vs**  | **vs**  |
| +SOD**   | +SOD\[GLN\]** | [GLN\]** |         |         |         |
|          |               |          | **C**   | **A**   | **C**   |
+----------+---------------+----------+---------+---------+---------+
| **A.     |               |          |         |         |         |
| Mean     |               |          |         |         |         |
| Change   |               |          |         |         |         |
| in Total |               |          |         |         |         |
| IPN      |               |          |         |         |         |
| Calories |               |          |         |         |         |
| \[kca    |               |          |         |         |         |
| l/wk\]** |               |          |         |         |         |
+----------+---------------+----------+---------+---------+---------+
| **\[n =  | **\[n =       | **\[n    |         |         |         |
| 16\]**   | 16\]**        | =9\]**   |         |         |         |
+----------+---------------+----------+---------+---------+---------+
| **-      | **-5751.2**   | **-      | **-3    | **-1    | **-1    |
| 4338.3** |               | 2633.3** | 117.9** | 412.9** | 705.0** |
|          |               |          |         |         |         |
|          |               |          | *       | **\[0.0 | **\[0.  |
|          |               |          | *\[\<0. | 436\]** | 005\]** |
|          |               |          | 001\]** |         |         |
+----------+---------------+----------+---------+---------+---------+
| **B.     |               |          |         |         |         |
| Mean     |               |          |         |         |         |
| Change   |               |          |         |         |         |
| in IPN   |               |          |         |         |         |
| or SLE   |               |          |         |         |         |
| F        |               |          |         |         |         |
| requency |               |          |         |         |         |
| \[       |               |          |         |         |         |
| d/wk\]** |               |          |         |         |         |
+----------+---------------+----------+---------+---------+---------+
| **\[n =  | **\[n =       | **\[n =  |         |         |         |
| 16\]**   | 16\]**        | 9\]**    |         |         |         |
+----------+---------------+----------+---------+---------+---------+
| **-3.0** | **-4.2**      | **-2.0** | *       | *       | *       |
|          |               |          | *-2.2** | *-1.2** | *-1.0** |
|          |               |          |         |         |         |
|          |               |          | *       | **\[0.0 | **\[0.  |
|          |               |          | *\[\<0. | 478\]** | 025\]** |
|          |               |          | 001\]** |         |         |
+----------+---------------+----------+---------+---------+---------+
| Source   |               |          |         |         |         |
| of       |               |          |         |         |         |
| table:   |               |          |         |         |         |
| see      |               |          |         |         |         |
| footnote |               |          |         |         |         |
| to Table |               |          |         |         |         |
| 6.       |               |          |         |         |         |
|          |               |          |         |         |         |
| a,b,and  |               |          |         |         |         |
| c) : See |               |          |         |         |         |
| footnote |               |          |         |         |         |
| to Table |               |          |         |         |         |
| 6.       |               |          |         |         |         |
+----------+---------------+----------+---------+---------+---------+

> **4. Number of Subjects Weaned off Total IPN (Table 8)**
>
> In their Table 11-6 of the Clinical Report, the sponsor presented a
> summary of categorical change of frequency of IPN or SLE
> administration from Week 2 to Week 6 for the ITT Population by
> Treatment arm. The frequency change was split into 3 categories with
> small number of patients per cell. The reviewer has elected to focus
> on the 100% reduction category (Table 8).
>
> **NOTE: These data seem to be hypothesis-generating**. One important
> issue is the degree of standardization of procedures across patients
> to determine **when IPN requirement volume is to be decreased** and
> when is the patient to be weaned off IPN (completely). The sponsor
> explained that IPN requirements were to be reduced when the patient
> demonstrated **all 3** **of the following**: 1. Ability to hydrate; 2.
> Ability to maintain serum electrolytes within the limits of normal
> range with or without the use of enteral electrolyte supplement(s);
> and 3. Ability to sustain an appropriate body weight. But each one of
> these parameters of evaluation may be subject to different definitions
> and varied interpretations. These parameters are hard to standardize.
> To be more valuable, the information should include a) the proportion
> of patients that are weaned off IPN; and b) more importantly, the
> proportion of those **who remain off IPN long-term**.
>
> Nonetheless, when examining these initial data, it is worth mentioning
> that including percentages of patients when the total Study Population
> is so small is not very helpful. From the comparison of Groups B (the
> test medication arm, including 3 co-therapies) to the control arm
> (Group C, which includes 2 co-therapies, SOD and GLN, but no rh-GH),
> the conclusion may be reached that **rh-GH in co-therapy with SOD and
> GLN might result in more patients that could be weaned off Total
> IPN.** Confirmation of these findings would be important.

+-----------------------+-----------------------+-----------------------+
| **Table 8**           |                       |                       |
|                       |                       |                       |
| **Study IMP20317**    |                       |                       |
|                       |                       |                       |
| **Categorical Change  |                       |                       |
| (100% reduction) in   |                       |                       |
| Frequency of IPN or   |                       |                       |
| SLE Administration    |                       |                       |
| from Week 2 to Week   |                       |                       |
| 6**                   |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **ITT POPULATION**    |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **Groups**            |                       |                       |
+-----------------------+-----------------------+-----------------------+
| **A**                 | **B**                 | **C**                 |
|                       |                       |                       |
| **rhGH + SOD**        | **rhGh + SOD\[GLN\]** | **SOD\[GLN\]**        |
+-----------------------+-----------------------+-----------------------+
| **\[n = 16\]**        | **\[n = 16\]**        | **\[n = 9\]**         |
+-----------------------+-----------------------+-----------------------+
| **5**                 | **7**                 | **1**                 |
+-----------------------+-----------------------+-----------------------+
| **\[5\]\***           | **\[8\]\***           | **\[1\]\***           |
+-----------------------+-----------------------+-----------------------+
| In the Footnote to    |                       |                       |
| Table 11-6 of the     |                       |                       |
| Clinical Report, the  |                       |                       |
| sponsor explained     |                       |                       |
| that the number of    |                       |                       |
| subjects with a 100%  |                       |                       |
| reduction in IPN or   |                       |                       |
| SLE administration is |                       |                       |
| greater than the      |                       |                       |
| number of subjects in |                       |                       |
| the TR population     |                       |                       |
| because some subjects |                       |                       |
| continued to receive  |                       |                       |
| hydration fluid.      |                       |                       |
|                       |                       |                       |
| \* A, B, and C,       |                       |                       |
| patients who remained |                       |                       |
| weaned off IPN at 16  |                       |                       |
| weeks                 |                       |                       |
+-----------------------+-----------------------+-----------------------+

> **5. Comparison between the Treatment Period (Week 2 to Week 6) and
> the Follow-up Period (Week 6 to Week 18)**
>
> The sponsor presented data (Table 11-9, volume 1, page 118 of the
> Clinical Report), summarizing the change in weekly volume, calories
> and frequency of IPN used during Week 6 versus Week 18, adjusting for
> the change from Week 2 to Week 6 for the ITT Study Population It is
> noted that residuals from the ANCOVA on the original scale were not
> normally distributed. As already mentioned, the change in primary and
> secondary efficacy parameters was analyzed adjusting for the change
> during the Treatment Period as a covariate. These analyses demonstrate
> that all groups increased their IPN requirements similarly during the
> Follow-up Period. These data are interpreted as showing that the
> persistence of treatment effects during the Follow-up Period was
> similar for all 3 treatment arms.
>
> **6. Adjustments for Effects of Covariates on Primary and Secondary
> Endpoints**
>
> According to the Clinical Report (volume 1, page 121) covariates that
> were assessed for the ITT Study Population included: age; sex;
> **weight,** time since diagnosis of SBS; time since last resection (\<
> 12 months or \>= 12 months); **length of residual jejunum-ileum;
> presence of an intact colon**; and **IPN volume history** (including
> weekly IPN volume, calories, and frequency).

-   The analyses revealed that the Total Weekly IPN volume results were
    influenced significantly by patients'

```{=html}
<!-- -->
```
-   **weight \[p\<0.001\]**. Subjects with higher body weight
    experienced greater reductions in total weekly IPN volume than
    subjects with lower body weights.

-   **length of residual volume \[p = 0.028\].** Subjects with longer
    residual bowel had larger decreases in Total IPN volume than those
    with shorter residual bowel.

-   **IPN volume history \[p = 0.044\].** Subjects with a history of
    higher IPN volume requirements experienced greater decreases in IPN
    volume during the Treatment Period than those with a history of
    lower IPN volume requirements.

> \- **race \[p = 0.021\].** It was found that Caucasians responded to
> treatment better than non-Caucasians. The sponsor brings attention to
> the fact that only 9 out of 41 subjects were non-Caucasians.
>
> **NOTE :** In all cases with a significant covariate, the effect of
> the test medication arm (group B, rhGh + SOD\[GLN\] **remained highly
> significant.**[^46]
>
> According to the Clinical report, Total IPN calorie results for the
> ITT Study Population were not influenced by the inclusion of any of
> the covariates. **Only patients' weight** **\[0.029\] influenced the
> treatment results** for the frequency of administration of IPN or SLE
> for the ITT Study Population. Covariate analyses for the E-E Study
> Population yielded results similar to those for the ITT Population.
>
> **7. Other**

-   Drug Dose, Drug Concentration, and Relationships to Response were
    not analyzed because drug concentration data were not collected.

-   Drug-Drug and Drug-Disease Interactions were not analyzed
    statistically. In general the data seemed to indicate that 4 weeks
    of 0.10 mg/kg/d rh-GH **did not induce hyperglycemia** in subjects
    with SBS that were dependent on IPN.

### D. Efficacy Conclusions

> The question of efficacy is settled by comparing the active
> rh-GH-containing arm,
>
> Group B (rh-GH + SOD\[GLN\]) to Group C, the control. The group B
> treatment arm includes the recombinant human growth hormone test
> medication and was administered in co-therapy with two additional
> components, the specialized/standardized oral diet (SOD) and glutamine
> \[GLN\]. Group C is an adequate control because this treatment arm is
> similar in composition to B with regards to SOD and GLN but contains
> rh-GH placebo instead of the active hormone. Therefore, the comparison
> B vs. C is valid and meaningful.
>
> Analyses using the prospectively stipulated primary endpoint of
> efficacy demonstrated that the administration of rh-GH in co-therapy
> with SOD + \[GLN\] was associated with a significant reduction
> (**therapeutic gain = 3.9 liters per week**) in the Total IPN volume
> requirement. The difference between B and C was highly significant (p
> \< 0.001, for both the Intent-To-Treat as well as the Evaluable- for-
> Efficacy Study Populations).

## VII. Integrated Review of Safety

### A. Brief Statement of Conclusions

> From the available information, it is reasonable to conclude that
> overall, there are no major safety concerns with the use of rhGH in
> co-therapy with GLN (and SOD) in patients with SBS treated for up to
> 16 weeks
>
> The reviewer agrees with the sponsor that the safety profile of
> rh-GH + SOD\[GLN\] appears to be similar to the safety profile of
> rh-GH + SOD plus placebo glutamine. It is to be noted that the sponsor
> **does not propose to revise the currently approved labeling** to
> include safety data related to the use of the drug in SBS patients.
> Because of the above-noted information, **the reviewer agrees that
> this approach is reasonable and acceptable.**

### B. Description of Patient Exposure

> In section 12.1, page 129 of the Clinical Report, the sponsor
> summarized the total exposure information. Total exposure of subjects
> to rhGH was a maximum of 28 days at 0.10 mg/kg/d (32 subjects)[^47].

### C. Methods and Specific Findings of Safety Review 

-   During the Baseline Period, 88% of rh-GH +SOD\[GLN\] subjects and
    88% of those receiving rh-Gh + SOD reported at least one Baseline
    Sign and Symptom (BSS) in comparison to 78% of those in the
    SOD\[GLN\] Group.

-   There were no deaths in this trial.

```{=html}
<!-- -->
```
-   The most frequently reported BSSs included edema, fatigue, and
    gastrointestinal disorders, **all of which are signs and symptoms of
    SBS**.

-   During the treatment period, all of the subjects receiving rh-GH +
    SOD\[GLN\], as well as all of those treated with rh-GH+SOD reported
    at least one AE as compared with 89% of SOD\[GLN\] subjects.

-   The proportion of subjects experiencing at least one
    treatment-related AE in the rh-GH + SOD\[GLN\], rh-GH + SOD[^48],
    and SOD\[GLN} treatment groups was 88%, 94%, and 22%, respectively.
    Although 94% vs 22% appears quite different, these percentages are
    calculated from small number of patients. These are difficult to
    interpret. However, see below.

-   None of the SAE (**none reported in subjects in Group B consisting
    of rh-GH given in co-therapy with glutamine to patients receiving a
    specialized oral diet**) were considered related to test medication.

-   The proportion of subjects experiencing at least one AE during the
    Follow-up Period was similar among the 3 treatment groups.

-   The occurrence of other AEs occurring in subjects in the rh-GH +
    SOD\[GLN\] or rh-GH + SOD treatment groups was similar to the rates
    reported in the package insert for Serostim® except for **edema and
    application (injection) site disorders,** which were reported more
    often in IMP20317.

-   As noted by the sponsor, variations in laboratory values are
    expected in this subject population due to their underlying
    conditions and their dependence on parenteral nutrition. The
    fluctuations in laboratory values were similar across all 3
    treatment arms. No clinically significant pattern was detected.

### D. Adequacy of Safety Testing

Giving the fact that **SBS is an orphan indication** and that rh-GH is
already approved for another indication (**treatment of AIDS wasting or
cachexia**), the reviewer believes that the safety testing in NDA 21-597
was, all in all, adequate.

Safety testing was adequate both, with respect to exposure as well as
the type of clinical and laboratory assessments that were carried out.

**NOTE:** For completeness purposes, the reviewer includes here a brief
summary of three recent publications on the subject matter of safety
when using growth hormone long-term, which should be considered if the
drug is approved for the treatment of Short Bowel Syndrome. This is
because, for this proposed indication, the drug may need to be
administered for prolonged periods of time, perhaps for the rest of the
patient\'s life. It is worth noting that long-term safety matters with
growth hormone require further discussion.

-   The first is a pre-clinical study aimed to gain a clearer
    understanding of the interaction between GH and tumor cells in vivo.
    [^49]It was concluded that overall, GH synergistically promotes
    carcinogen-induced hepatocarcinogenesis in both sexes of
    GH-transgenic mice by stimulating tumor cell proliferation.

-   The other two publications referred to clinical/epidemiologic
    findings.

> \- In the first, Bramnert et al.[^50] examined both short-term (1 wk)
> and long-term (6 months) effects of a low-dose GH replacement therapy,
> in comparison to placebo, on whole body glucose and lipid metabolism
> and on muscle composition. It was concluded that replacement therapy
> with a low-dose GH in GH-deficient adult subjects is associated with a
> sustained deterioration of glucose metabolism as a consequence of the
> lipolytic effect of GH, resulting in enhanced oxidation of lipid
> substrates. Also, a shift toward more insulin-resistant type II X
> fibers was seen in muscle \[glucose metabolism should be carefully
> monitored during long-term GH replacement therapy\].

-   In the second, Swerdlow and co-workers[^51], did a cohort study to
    investigate cancer incidence and mortality in 1848 patients in the
    UK who were treated during childhood and early adulthood with human
    pituitary GH during the period from 1959 to 1985. Patients were
    followed up for cancer incidence to December, 1995 and for mortality
    to December, 2000. Risk of cancer control was compared with that in
    the general population, controlling for age, sex, and calendar
    period. The authors\' findings included a highly raised risk of
    colorectal cancer. Their interpretation of their findings was that,
    although based on small numbers, the risk of colorectal cancer is of
    some concern and further investigation in other cohorts is needed.

-   Although this information is included here for completeness, the
    reviewer believes that evidence that GH administration is associated
    with an increased risk of colorectal cancer needs confirmation.

## VIII. Dosing, Regimen, and Administration Issues

In clinical trial IPM20317, the sole evidence of effectiveness presented
by the sponsor, only one dose level of the subcutaneously administered
hormone (0.1 mg/kg/d) was tested. Based on results of this trial, the
sponsor proposes to revise the DOSAGE AND ADMINISTRATION Section of the
labeling to include the following wording: \"In patients with Short
Bowel Syndrome (SBS), Serostim® should be administered at a dose of 0.1
mg/kg subcutaneously daily to a maximum of 8 mg daily\" . Based on
literature publications made use of throughout the current review, the
reviewer does not believe that the dose has been adequately assessed.

-   In a recently published well-designed clinical trial (Study No. 7 in
    Table 2 of the current review), the combination \"**high-dose\" GH
    (defined as 0.14 mg/kg/d)** and **glutamine** did not increase body
    weight, lean body mass, fat mass, and bone mass significantly
    compared to placebo treatment.

-   An even more recently but also well-designed and apparently
    well-executed published trial (Study No. 9 in Table 2 of the current
    review) showed that treatment with **GH at the \"low-dose\" of 0.05
    mg/kg/d** increased intestinal absorption of energy, nitrogen, and
    fat. In this study, other parameters that increased were body
    weight, lean body mass, D-xylose absorption, insulin-like growth
    factor-1 and insulin-like growth factor binding protein 3. This
    study reported also that uptake of GH binding protein decreased
    without any apparent adverse event.

> **NOTE:** In spite of the above, with the evidence at hand, it is not
> possible to rule out the possibility that the difference in efficacy
> results seen between the sponsor\'s and other GH preparations are due
> to methodological (differences in primary and secondary efficacy
> endpoints used in the clinical trials and the way the clinical trials
> were actually executed) rather than differences due to dose. It is
> worth reiterating that rh-GH, at the subcutaneously administered dose
> of 0.1 mg/kg/d, was shown to be safe and effective when assessed under
> the experimental conditions in Study IMP20317. The reviewer believes
> that if issues such as replicability/generalizability, and adequacy of
> the primary endpoint of efficacy are resolved, the issue of the dose
> recommendation might be resolved by the sponsor agreeing to a Phase IV
> commitment to assess the efficacy of low-dose rh-GH in the treatment
> of SBS, under a mutually agreeable, well-designed trial.

## IX. Use in Special Populations

> Although it is always important to address questions regarding use in
> special populations, short bowel syndrome is an orphan indication. The
> total number of SBS patients who were totally IPN-dependent who were
> randomized into one of the 3 arms of Study IMP20317 and received test
> medication was too small (n = 16). Therefore, evaluation of the use of
> the drug in special populations is not very helpful.
>
> It is worth noting that the currently approved Package Insert,
> PHARMACOKINETICS Section, includes information on Pediatric Patients,
> Gender, those with Renal Insufficiency, and those with Hepatic
> Insufficiency; but data for race are not available. In addition, in
> the PRECAUTIONS Section, Information on Pregnancy, Nursing Women,
> Pediatric Use and Geriatric Use, is included.

### X. OTHER

> There are three issues, already noted during this review, that are
> worthy of further discussion. The first is the reduction in Total IPN
> volume, in liters per week, as the primary endpoint of efficacy. The
> second is the contribution of glutamine as co-therapy and the third is
> the role of the specialized diet. After all, the proposed (additional)
> use in the INDICATIONS AND USAGE Section of the labeling reads
> \"...for the treatment of Short Bowel Syndrome in patients receiving
> specialized nutritional support. Serostim^®^ therapy should be used in
> conjunction with optimal management of Short Bowel Syndrome\".

-   Long-term Total Parenteral Nutrition (TPN) is a supportive rather
    than curative therapy but it is life-sustaining and remains the
    current standard of care for patients with severe SBS. In addition
    to extraordinary costs, it is very important to recognize the
    complications that may accompany TPN . These complications include
    hepatic dysfunction, progressive renal insufficiency, bone
    demineralization, catheter sepsis, and numerous nutrient
    deficiencies. **There is no question that weaning a patient off**
    **TPN therapy is a very significant clinical achievement** .But if
    one demands this as an endpoint, is this expecting too much of the
    drug? One question raised by the data in NDA 21-597 is: in the
    absence of data demonstrating that patients are weaned off TPN, what
    is considered a clinically important reduction in Total IPN volume
    (primary efficacy endpoint) and a reduction in Total IPN calories
    and IPN or SLE Frequency (secondary efficacy endpoints)?

-   As mentioned in Section I of this review, glutamine (GLN) exerts
    important morphological and functional effects on the bowel. These
    effects appear to be similar to those of GH. GLN is a major fuel
    source for both the enterocytes and the colonocytes [^52] and this
    amino acid is necessary for the maintenance of intestinal structure.
    In critically ill patients unable to take adequate enteral nutrition
    , the addition of GLN to standard TPN solutions prevent TPN-induced
    gut permeability[^53]. Enteral rather than parenteral GLN has also
    been shown to induce trophic or regenerative effects on the
    bowel[^54]. But the effects of GLN in the clinic appear
    inconsistent. Based on evaluations by Dr. D. Price, FDA
    Statistician, in Study IMP20317, the contribution of glutamine to
    the effect observed with growth hormone is not substantial.

-   The current recommendation is to maintain patients with SBS with
    residual colon on a high-carbohydrate, low-fat diet. Such a diet
    results in greater caloric absorption than a high-fat,
    low-carbohydrate diet because malabsorbed CHOs are salvaged in the
    colon, whereas malabsorbed fatty acids are not. In addition, fat
    restriction enhances mineral absorption and decreases oxalate
    hyperabsorption. However, in the experience of many investigators,
    patients dislike low-fat diets and sometimes need to consume fat in
    order to maintain their weight. It is worth noting that a high-fat
    diet did not increase fecal weight in SBS patients with residual
    colon in comparison to high-CHO diets and that the evidence
    supporting a low-fat diet is based on short-term balance studies,
    where compliance is demanded, rather than on body weight response to
    various dietary prescriptions, where compliance is questionable. A
    well-designed, well-executed trial concluded that conjugated bile
    acid replacement therapy should be part of the armamentarium for the
    treatment of selected patients with the short bowel syndrome.[^55]
    Although further studies are needed before the composition of a
    standard diet can be recommended (and this may depend upon the
    patient\'s nutritional status), the important issue concerning the
    use of an SOD in Study IMP20317 is standardization of the
    nutrient/caloric intake so that it cannot be considered a
    potentially confounding variable. This issue is further addressed in
    Dr. Price\'s statistical review.

## XI. Conclusions and Recommendations

### A. Conclusions

> The sponsor of NDA 21-597 has presented evidence from a single,
> 41-patient study that subcutaneously administered rh-GH, at the daily
> dose of 0.1 mg/kg for 4 weeks, effectively reduces the total IPN
> volume requirement in IPN-dependent SBS patients. However, the
> clinical relevance of this endpoint (reduction in Total IPN volume
> requirement per week) must be established prior to approval..

### B. Recommendations

> NDA 21-597 deficiencies must be addressed.
>
> **FINAL NOTE**: Regulatory discussion on the one study approach can be
> found in the following FDA document: **Guidance for Industry.
> Providing Clinical Evidence of Effectiveness for Human and Biological
> Products.** U.S. Department of HHS, FDA, CDER, CBER, May 1998,
> Clinical 6 \[Internet at
>
> http://www.fda.gov/cder/guidance/index.htm\`

[^1]: Serostim^®^ is produced by a mammalian cell line (mouse C127) that
    has been modified by the addition of the human GH gene. Serostim^®^
    is secreted directly through the cell membrane into the cell culture
    medium for collection and purification. Serostim^®^ is highly
    purified preparation. Biological potency is determined by measuring
    the increase in the body weight induced in hypophysectomized rats.

[^2]: There exist human GH, methionyl human GH, bovine somatotropin,
    porcine somatotropin, etc.

[^3]: The product information notes that, for patients treated in
    open-label extension studies, no significant additional efficacy was
    observed beyond 12 weeks. There are no data available from
    controlled studies for patients that start, stop, ands re-start
    treatment. Concomitant anti-viral therapy is necessary. It is also
    noted that the continued use of Serostim^®^ treatment should be
    reevaluated in patients who continue to lose weight in the first two
    weeks of treatment.

[^4]: [Pediatric use:]{.underline} In two small studies, 11 children
    with HIV-associated failure to thrive were treated subcutaneously
    with human growth hormone. In one study, five children (age range, 6
    to 17 years) were treated with 0.04 mg/kg/day for 26 weeks. In a
    second study, six children (age range, 8 to 14 years) were treated
    with 0.07 mg/kg/day for 4 weeks. Treatment appeared to be well
    tolerated in both studies. These preliminary data collected on a
    limited number of patients with HIV-associated failure to thrive
    appear to be consistent with safety observations in growth hormone
    treated adults with AIDS wasting.

[^5]: [Geriatric use:]{.underline} Clinical studies with Serostim^®^ did
    not include sufficient number of subjects aged 65 and over to
    determine whether they respond differently from younger subjects.
    Elderly patients may be more sensitive to growth hormone action, and
    may be more prone to develop adverse reactions. Thus, dose selection
    for an elderly patient should be cautious, usually starting at the
    lower end of the dosing range.

[^6]: This is an approximate length as most methods of residual
    intestine measurement (such as radiologic contrast studies,
    pathology of the resected specimen, and perioperative measurement of
    unweighted intestine) are not especially accurate. Because
    absorption is related to the amount of residual intestine, it is
    more important to document the amount of remaining, viable
    intestine.

[^7]: Buchman, A.L. et al. AGA Technical Review on Short bowel Syndrome
    and Intestinal Transplantation. Gastroenterology 124:1111-1134
    (2003)

[^8]: Malabsorption of a single nutrient, such as vitamin B~12~ or the
    need for a special diet to exclude a damaging component such as
    gluten, is not included within this definition.

[^9]: Such a diet results in greater caloric absorption than a high-fat,
    low-carbohydrate diet because malabsorbed carbohydrates are salvaged
    in the colon whereas malabsorbed fatty acids are not. In addition,
    fat restriction enhances mineral absorption and decreases oxalate
    hyperabsorption.

[^10]: Lennard-Jones, J.E. Review article: practical management of the
    short bowel. Aliment. Pharmacol. Ther. 8:563-577 (1994).

[^11]: Sham J. et al. Epidermal growth factor improves nutritional
    outcome in a rat model of short bowel. J. Pediatric Surg. 37:765-769
    (2002)

[^12]: Litvak, D.A. et al. Characterization of two novel proabsorptive
    peptide YY analogs, BIM-43073D and BIM-43004C. Dig. Dis. Sci. 44:
    643-648 (1999)

[^13]: Wood, J.G. et al. Neurotensin stimulates growth of small
    intestine in rats. Am J Physiol , 255: G813-G817 (1988)

[^14]: Mice that overexpress glycine-extended glycine show a large
    increase in colonic mucosa thickness and colonic proliferation
    \[Koch, T.J. Overexpression of glycine-extended gastrin in
    transgenic mice results in increased colonic proliferation. J Clin
    Invest 103:1119-1126 (1999)\]

[^15]: Peptide YY, like GLP-2, is produced by the L cells of the ileum
    and colon; it slows gastric emptying and small bowel transit and may
    be responsible for the \"ileal\" and \"colonic\" brakes
    \[Nightingale, JMD et al. Disturbed gastric emptying in the short
    bowel syndrome. Evidence for a \"colonic brake\" Gut 34: 1171-1176
    (1993)\]

[^16]: TGF-α \"knock-out\" mice have an increased susceptibility to
    injurious agents to the colon \[Egger, B. et al. Mice lacking
    transforming growth factor α have an increased susceptibility to
    dextran sulfate-induced colitis. Gastroenterology 113: 825-832
    (1997)\] but they do not have an increased susceptibility to
    indomethacin-induced small intestinal injury \[Macdonald, C.E. et al
    Transforming growth factor α knockout mice have smaller small
    intestines, larger large intestines, but no increased sensitivity to
    NSAID-induced small intestinal injury. Gut 42 (suppl. 1): A3
    (1998)\]

[^17]: Playford, R.J. et al. Effects of keratinocyte growth factor (KGF)
    on gut growth and repair. J. Pathol. 184: 316-322 (1998)

[^18]: Jeppesen, P. B. et al Glucagon-like Peptide 2 improves Nutrient
    Absorption and Nutritional Status in Short- Bowel Patients With No
    Colon. Gastroenterology 120: 806-815 (2001)

[^19]: Warner, B. W. Editorial: GLP-22 as therapy for the short bowel
    syndrome. Gastroenterology 120:1041-1048 (2001)

[^20]: Lund PK. Molecular basis of intestinal adaptation: the role of
    the insulin-like growth factor system. Ann NY Acad Sci 859: 18-36
    (1998)

[^21]: Peterson, et al. GH elevates serum IGF-1 levels but5 does not
    alter mucosal atrophy in parent rally fed rats. Am J Physiol 272:
    G1100-G1108 (1997)

[^22]: Gu Y et al. Effects of growth hormone and glutamine supplemented
    parenteral nutrition on intestinal adaptation in short bowel rats.
    Clin Nutr 20: 159-166 (2001)

[^23]: Vanderhoof JA, et al. Growth hormone and glutamine do not
    stimulate intestinal adaptation following massive small bowel
    resection in the rat. J Pediatr Gastroenterol Nutr 25: 327-331
    (1997)

[^24]: Lund PK et al (locus cited) (1998)

[^25]: Snibson KJ et al. Overexpressed growth hormone (GH)
    synergistically promotes carcinogen-initiated liver tumour growth by
    promoting cellular proliferation in emerging hepatocellular
    neoplasms in female and male GH-transgenic mice. Liver 21(2):
    149-158 (2001)

[^26]: \[Ogilvy-Stuart AL. Safety of growth hormone after treatment of a
    childhood malignancy. Horm Res 44 (Suppl 3): 73-79 (1995); Ng ST et
    al. Growth hormone treatment induces primary gland hyperplasia in
    aging primates. Nat Med 3: 1141-1144 (1997)\]

[^27]: Jung Sung-Eun, et al. Combined Administration of Glutamine and
    growth Hormone Synergistically Reduces Bacterial Translocation in
    Sepsis. J Korean Med sci 18: 17-22 (2003)

[^28]: Under Dosage and Administration, the currently approved Package
    Insert indicates that Serostim^®^ \[somatropin (rDNA origin) for
    injection\] should be administered to AIDS wasting patients
    subcutaneously daily at bedtime according to the following dosage
    recommendations : (information simplified by reviewer)

    Weight Range SC Daily Dose

    (Kg) (mg)

    \> 55 6

    5

    > 35-45 4

[^29]: Buchman AL, et al. \[locus cited, under Footnote 7\] (2003)

[^30]: Nightingale, JMD, Editor. Intestinal Failure, GMM, San Francisco,
    CA (2001)

[^31]: Szkudlarek, J. et al. Effect of high dose growth hormone with
    glutamine and no change in diet on intestinal absorption in short
    bowel patients: a randomized, double-blind, crossover,
    placebo-controlled study. Gut 47: 199-205 (2000).

[^32]: In the event of a patient\'s transient intolerance to oral
    intake, it was allowable for the dose to be delayed for up to 2 h
    until the patient was able to drink it.

[^33]: According to the information provided by the sponsor, the seed
    for subjects 101-135 at Site 01 was 55784. The seed for subjects
    201-203 at Site 01 was 55785. The seed for subjects 301-303 at Site
    02 was 55787.but only 3 subjects in total were randomized at Site 2.

[^34]: There were no laboratory measurements performed that would have
    unblinded the study.

[^35]: Each vial of test medication contained a two-part label
    consisting of a portion permanently attached to the vial and a
    tear-off portion that was attached to the patient\'s CRF.

[^36]: These packets had tear-off portions as above.

[^37]: IPN and SLE requirements for each patient were recorded daily
    during Week 2 through Week 6.

[^38]: For Week 18, summary data only for IPN frequency, volume, and
    calories were provided in the CRF on the basis of contact with the
    patient\'s local physician.

[^39]: Lot numbers TC0409, MMK641A2, and MON668B.

[^40]: Lot Numbers TC0396 and PLM99-34.

[^41]: \[ Byrne, TA. Et al. Advances in the management off patients with
    intestinal failure. Transplt Proc 28:2683-2690 (1996)\]

[^42]: For continuous covariates, the covariate was assessed by using
    Type I sums of squares.

[^43]: Model assumptions including the presence of covariate by
    treatment interactions were to be checked , and analyses were to be
    adjusted accordingly.

[^44]: According to the Clinical Report, a formal inferential analysis
    for safety parameters was not conducted.

[^45]: As previously noted, the primary outcome was analyzed utilizing
    an analysis of covariance model with baseline covariate. Pairwise
    comparison between the groups of interest were assessed utilizing
    Dunnett-Hsu test to control Type I error rate at 5%.

[^46]: In those instances with a significant covariate, the comparison
    of Group A to C remained significant only when weight was used as a
    covariate.

[^47]: Total exposure of subjects to rhGH placebo was a maximum of 28
    days at 0.10 mg/kg/d (9subjects).

[^48]: One rhGH + SOD subject discontinued from the trial during Week 5
    because of fungemia.

[^49]: Snibson KJ et al. Overexpressed growth hormone (GH)
    synergistically promotes carcinogen-initiated liver tumour growth by
    promoting cellular proliferation in emerging hepatocellular
    neoplasms in female and male GH-transgenic mice.

[^50]: Bramnert M et al. Growth Hormone replacement Therapy Induces
    Insulin Resistance by Activating the Glucose-Fatty Acid Cycle. J
    Clin Endocrinol Metab 88: 1455-1463 (2003)

[^51]: Swerdlow AJ et al. Risk of cancer in patients treated with human
    pituitary growth hormone in the UK, 1959-85: a cohort study. Lancet
    360: 273-277 (2002).

[^52]: Souba WW, et al. Glutamine metabolism by the intestinal tract.
    JPEN 9: 608-617 (1985)

[^53]: VanderHulst RRJ et al. Glutamine and the preservation of gut
    integrity. Lancet 341: 1363-1365 (1993).

[^54]: Klimberg VS et al. Prophylactic glutamine protects the intestinal
    mucosa from radiation injury. Cancer 66: 62-68 (1990); Klimberg VS
    et al. Oral glutamine accelerates healing of the small intestine and
    improves outcome after whole abdominal radiation. Arch Surg. 125:
    1049-1055 (1990)

[^55]: Gruy-Kapral C et al. Conjugated Bile Acid Replacement Therapy for
    Short-Bowel Syndrome. Gastroenterology 116: 15-21 (1999)