MP 5.01.06

Human Growth Hormone

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Medical Policy
Section Prescription Drugs	Original Policy Date 11/1/97	Last Review Status/Date Reviewed with literature search/6:2008
Issue 6:2008		Return to Medical Policy Index

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Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

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Description

Policy

Recombinant human GH therapy may be considered medically necessary for the following patients (see specific patient selection criteria in Policy Guidelines):

1. Children with proven GH deficiency
2. Children with height less than the 3rd percentile for chronologic age with chronic renal insufficiency
3. Patients with AIDS wasting
4. Adults with proven GH deficiency
5. Patients with Turner’s syndrome
6. Patients with growth failure due to Prader-Willi syndrome or Noonan Syndrome
7. Promotion of wound healing in burn patients
8. Prevention of growth delay in children with severe burns
9. Patients with short bowel syndrome receiving specialized nutritional support in conjunction with optimal management of short bowel syndrome (See also policy No. 2.01.48 for discussion of inpatient intestinal rehabilitation.)

The following FDA-approved indications are considered not medically necessary:

1. Pediatric patients born small for gestational age (SGA) who fail to show catch-up growth by age 2 years
2. Children with height standard deviation score of -2.25 or below

Investigational applications for recombinant human growth hormone therapy include, but are not limited to, the following:

• Constitutional delay (lower than expected height percentiles compared with their target height percentiles and delayed skeletal maturation when growth velocities and rated of bone age advancement are normal)
• In conjunction with GnRH (gonadotropin-releasing hormone) analogs as a treatment of precocious puberty
• GH therapy in older adults without proven deficiency
• Anabolic therapy except for AIDS provided to counteract acute or chronic catabolic illness (e.g., surgery outcomes, trauma, cancer, chronic hemodialysis, chronic infectious disease) producing catabolic (protein wasting) changes in both adult and pediatric patients.
• Anabolic therapy to enhance body mass or strength for professional, recreational or social reasons
• Glucocorticoid-induced growth failure
• Short stature due to Down's syndrome
• Treatment of altered body habitus (e.g., buffalo hump) associated with antiviral therapy in HIV-infected patients
• Treatment of obesity
• Treatment of cystic fibrosis
• Treatment of idiopathic dilated cardiomyopathy
• Treatment of juvenile idiopathic or juvenile chronic arthritis

Policy Guidelines

The numbered guidelines correspond to the indications listed in the Policy section above.

Medically Necessary Indications:

 

1. Both children and adults with proven GH deficiency are considered appropriate candidates for GH therapy.

 

For adults, proven GH deficiency is defined as:

 

For children, no criteria have been established for the laboratory diagnosis of GH deficiency, and criteria may vary regionally. In the absence of a strict evidence-based approach, it is recommended that plans develop criteria in conjunction with local pediatric endocrinologists. (See further discussion in Laboratory Diagnosis of GH deficiency in Rationale section.) The recommended dosage for children with GH deficiency is 0.3 mg/kg per week, divided into daily or 6 times per week injections. In children, GH therapy is typically discontinued when the growth velocity is less than 2 cm per year, when epiphyseal fusion has occurred, or when the height reaches the 5th percentile of adult height.

 

2. Chronic renal insufficiency is defined as a serum creatinine of greater than 1.5 mg/dL (or 1.4 for women and 1.7 for men) or a creatinine clearance < = 75 ml/min per 1.73 m-2 . In patients with chronic renal failure undergoing transplantation, GH therapy is discontinued at the time of transplant or when the growth velocity is less than 2 cm per year, when epiphyseal fusion has occurred, or when the height reaches the 5th percentile of adult height.

 

3. AIDS wasting is defined as a greater than 10% of baseline weight loss that cannot be explained by a concurrent illness other than HIV infection. Patients treated with GH must simultaneously be treated with antiviral agents. Therapy is continued until this definition is no longer met.

 

4. Adults with GH deficiency are defined as in No. 1 above. Only about 25% of those children with documented GH deficiency will be found to have GH deficiency as adults. Therefore, once adult height has been achieved, subjects should be retested for GH deficiency to determine if continuing replacement therapy is necessary. These transition patients who require further treatment are usually started at doses of 0.4 to 0.8 mg/day, and tittered to maintenance doses of 1.2 to 2.0 mg/day. Adults with GH deficiency not related to idiopathic deficiency of childhood (e.g., pituitary tumor, pituitary surgical damage, irradiation, trauma) are usually started at 0.1 to 0.3 mg/day; the dose is tittered to clinically desired end points (improved body composition, quality of life, reduction in cardiovascular risk factors), usually resulting in maintenance doses of 0.2 to 0.5 mg/day for men and 0.4 to 1.0 mg/day for women. The FDA cautions that the safety and effectiveness of GH therapy in adults aged 65 and over has not been evaluated in clinical studies. Therefore, it is noted that elderly patients may be more sensitive to the action of GH therapy and may be more prone to develop adverse reactions.

 

5. Turner’s syndrome is defined as a 45, XO genotype. *

 

6. Prader-Willi syndrome is a genetic disorder characterized by a microdeletion in the long arm of chromosome 15. Clinically, the syndrome presents as a complex multisystem disorder characterized by excessive appetite, obesity, short stature, characteristic appearance, developmental disability, and significant behavioral dysfunction. GH deficiency has been demonstrated in most tested patients with Prader-Willi syndrome.

 

7. GH therapy for burn patients should be limited to those patients with 3rd-degree burns.

 

8. Children with severe burns have been successfully treated with 0.05 to 0.2 mg/kg rhGH per day during acute hospitalization and for up to 1 year after burn.

 

9. Growth hormone for patients with short bowel syndrome should be limited to patients receiving specialized nutritional support in conjunction with optimal management of short bowel syndrome. Specialized nutritional support may consist of a high-carbohydrate, low-fat diet adjusted for individual patient requirements. Optimal management may include dietary adjustments, enteral feedings, parenteral nutrition, fluid and micronutrient supplements. Zorbtive is administered daily at 0.1mg/kg subcutaneously up to 8 mg/day. Administration of Zorbtive for longer than 4 weeks has not been adequately studied per the FDA indications. See also policy No. 2.01.48  for discussion of inpatient intestinal rehabilitation.

Not Medically Necessary Indications:

 

1.  Pediatric patients born small for gestational age. There are no established criteria for small for gestational age or “catch-up” growth. However, in the data submitted to the FDA as part of the approval process, the mean height of enrolled patients was at least 2 standard deviations below the mean. Absence of catch-up growth was defined as a height velocity below 1 standard deviation score, adjusted for age.

 

2. Pediatric patients with short stature. "Short stature" has been defined by the American Association of Clinical Endocrinologists and the Growth Hormone Research Society as height more than 2 standard deviations (SD) below the mean for age and sex. The FDA-approved indication is for children with a height standard deviation score (SDS) of -2.25 below the mean. Using this proposed definition, approximately 1.2% of all children would be defined as having idiopathic short stature and considered potentially treatable under these indications. Note that this indication is considered not medically necessary.

Benefit Application

Rationale

The following discussion focuses on the most controversial aspects of GH use.

Laboratory Diagnosis of GHD

 

Diagnosing GHD in children remains an area of confusion and disagreement. As a result, guidelines remain vague. For example, both the 2003 American Association of Clinical Endocrinologists (AACE) guidelines and the 2000 consensus guidelines published by the GH Research Society state that diagnosis is a multifaceted process involving clinical, auxological, radiological, and biochemical assessment. These guidelines provide an informed discussion of various measures, but no proposal of specific criteria.

 

Regarding biochemical testing alone, there is little agreement on specific criteria within the pediatric endocrinology community. (1, 2) Some of the reasons include:

 

These areas of uncertainty have led some investigators and clinicians to abandon the use of provocative testing as the sole diagnostic for GHD, and instead base diagnoses on a combination of clinical and diagnostic test information. These often include:

 

• IGF-1 testing as a screen. However, approximately 30% of GHD patients have normal IGF-I and approximately 30% of short GH-sufficient children have low IGF-I.
• IGF-I in combination with a provocative test.
• Provocative testing.
• MRI. In general, sensitivity and specificity are moderate. However, the presence either of an ectopic posterior pituitary lobe or the association of a hypoplastic pituitary stalk and a hypoplastic anterior pituitary lobe is highly predictive of GHD. MRI is recommended for any pediatric patient with the provisional diagnosis of GHD.
• Radiologic bone age.
• Standard auxologic measurements such as height SDS, height velocity, and comparison of predicted final height and mid-parental height.
• Clinical features suggesting GHD or genetic conditions associated with severe short stature.

 

However, it should be noted that for the purposes of this policy, relying on auxologic measurements alone is inadequate to document GH deficiency. This policy is based on the premise that GH would be considered medically necessary as a replacement therapy for GH deficiency, and not medically necessary when used as treatment of short stature in the absence of GH deficiency. For example, as discussed further below, treatment of short stature without accompanying GH deficiency is generally considered not medically necessary due to the lack of a functional impairment.

GH Use in Short-Stature Children Alone Without Documented GH Deficiency or Underlying Pathology

 

In July 2003, Humatrope was, as noted, approved for use in non-GH-deficient short stature (defined for this indication as an SDS of -2.25 below the mean). Recommendation for approval was supported by data indicating a significant increase in final height with GH treatment compared to placebo; average increases ranged from 1.25 to 2.8 inches, depending on the trials, which differed in patient baseline characteristics, GH dose, administration, and length of treatment. For example, 1 randomized phase III trial (GDHC), which treated children with a height SDS of -2.25 or less with GH or placebo for an average of 4.43 years, found a statistically significant GH treatment effect on final height. Only 27% of placebo-treated patients and 42% of Humatrope-treated patients completed the study. An FDA analysis of final height estimated a treatment effect of 1.25 inches (adjusted for baseline predicted height) with a 95% CI of 0.1 to 2.4 inches. The manufacturer reported an estimate of a 2-inch gain for GH treatment over placebo based on a separate post hoc analysis that was undergoing further review by the FDA. Analysis of final height could only be conducted in 46% of 71 patients, including 8 patients who discontinued treatment, and may therefore be biased. Study E001 randomized 3 doses of Humatrope to children with height SDS of -2.0 or less. Final height was assessed in a long-term extension (mean 6.47 years) of this study for 21% of 239 patients. This subgroup achieved a height gain of 2.1 to 2.8 inches over baseline- predicted height; the increased effect in this trial compared to GDHC may be due to differences in starting age and Tanner stage, dose, longer follow-up, or a higher frequency of GH administration. In addition, a recent meta-analysis of 10 controlled and 28 uncontrolled trials estimate a benefit on adult height of 1.6 to 2.4 inches. (3)

 

While the Humatrope studies provide estimates for gains in adult height, the key consideration for determining the medical necessity of such treatment is any improvement in functional impairment. Functional impairments were not documented at the beginning or end of the study. While not an element of medical necessity, advocates of GH therapy often cite the potential psychosocial impairments associated with short stature. However, psychological data from questionnaires presented by the manufacturer were not correlated with change in growth rate or height standard deviation score. Thus data are inadequate from these studies to determine whether height increases in children with extreme short stature are associated with improved quality of life. In addition, other studies have suggested that short stature is only variably related to psychosocial morbidity. (4) There has been 1 controlled trial that examined the behavior of children without documented GH deficiency who were treated with GH due to idiopathic short stature. (5) Across measures of behavior, including IQ, self-esteem, self-perception, or parental perceptions of competence, there were no significant differences between the control and treatment groups, either at baseline or after 5 years of GH therapy. The authors concluded that while no psychosocial benefits of GH therapy have been demonstrated, likewise, no documented psychosocial ill effects of GH treatment have been demonstrated.

 

In January 1997, the American Academy of Pediatricians (AAP) published a document (6) that recommended the following patient selection criterion for children with short stature not associated with classic GH deficiency:

 

“Therapy with GH is medically and ethically acceptable in patients whose extreme short stature keeps them from participating in basic activities of daily living and who have a condition for which the efficacy of GH therapy has been demonstrated.”

 

In addition, the AAP noted:

 

“Numerous considerations argue against widespread administration of GH therapy to other short children. First, the therapy’s risk benefit ratio in this population is not established. There could be unknown long-term risks, and the treatment could result in either no increase or only an insignificant increase in final adult height. . . . Even if the clinical data show a positive risk benefit ratio, however, the benefits of GH therapy will inevitably remain somewhat elusive. Individual children may escape the stigma of being very short, but a group of very short children will always exist. On a broader scale, the best “therapy” for these children would be a campaign against the current prejudice against short people instead of an implicit medical reinforcement of such prejudice.”

GH Use in Small for Gestational Age Children

 

As noted in the Description section, in 2001, one GH preparation received FDA approval for treatment of children who are small for their gestational age. This FDA approval was based on 4 randomized, open-label controlled clinical trials. (7) Patients were observed for 12 months before being randomized to receive either 0.24 mg/kg/week or 0.48 mg/kg/week GH or no treatment for 24 months. After 24 months all patients received GH. In patients receiving the higher dosage of 0.48 mg/kg/wk, the patients' height improved from a baseline of -3.4 standard deviations to -1.7 standard deviations below the mean. In contrast, in the control group the standard deviation score improved to a lesser degree, from -3.1 to -2.9 standard deviations below the mean. The issues associated with this indication for GH are similar to those for other short-stature children without documented GH deficiency. There are no documented functional impairments associated with short stature and no data regarding final adult height in the control or treatment group. It should be noted that the dosage recommended for small for gestational age children, 0.48 mg/kg/week, is a supraphysiologic dose. For example, in patients with documented GH deficiency, in which the intent is to provide normal physiologic replacement levels of GH, the recommended dosage is only 0.24 mg/kg/week. There are very minimal data regarding the psychosocial outcomes of short pediatric or adult stature related to intrauterine growth retardation, and how these outcomes may be affected by GH therapy. As noted above, data are inadequate to document that short-stature youths have either low self-esteem or a higher than average amount of behavioral or emotional problems. (4, 6)

 

For both small for gestational age children and short-stature children, an additional strategy to achieve target adult heights is to combine GH therapy with gonadotropin hormone releasing (GnRH) analogs, which prolong the prepubertal growth period. The combined therapy is intended to increase the critical pubertal height gain by delaying the fusion of the epiphyseal growth plates, thus prolonging the period during which GH is active. This therapy has been suggested for children who are considered short when they enter puberty. (8-10)

Turner Syndrome

 

Short stature is almost universal in Turner's syndrome. Poor growth is evident in utero and further deceleration occurs during childhood and at adolescence. The mean adult height for those with Turner syndrome is 58 inches (4 ft 10 inches). Unlike Prader-Willi syndrome, GH deficiency is not seen. The FDA approvals for Humatrope and Nutropin were based on the results of randomized, controlled clinical trials that included final adult height as the outcome. A group of patients with Turner's syndrome given Humatrope at a dosage of 0.3 mg/kg/week for a median of 4.7 years achieved a final height of 146.0 +/- 6.2 cm (57.5 +/-2.25 inches) compared to an untreated control group who achieved a final height of 142.1 +/- 4.8 cm (56 +/- 2 inches). (11) The results with Nutropin were similar. (12) While the data regarding Turner's syndrome are somewhat unique in that final height is known, the clinical significance of a mean increase in height of 3.9 cm (1.75 inches) is unknown. It should also be noted that earlier initiation of GH therapy might results in more significant increases in adult height.

GH Therapy in Conjunction with GnRH Therapy as a Treatment of Precocious Puberty

 

Precocious puberty is generally defined as the onset of secondary sexual characteristics before 8 years of age in girls and 9 years in boys. Central precocious puberty is related to hypothalamic pituitary gonadal activation, leading to increase in sex steroid secretion, which accelerates growth and causes premature fusion of epiphyseal growth plates, thus impacting final height. Children with precocious puberty are often treated with GnRH (gonadotropin-releasing hormone) analogs to suppress the pituitary gonadal activity, to slow the advancement of bone age, and to improve adult height. Several long-term studies have reported that treatment with GnRH analogs is associated with improved adult height in most cases, particularly in those with the most accelerated bone age progression at treatment onset, the shortest predicted height, and the greatest difference between the target height and the predicted height. (13-15) In contrast, patients with a slowly progressive form in which the predicted height does not change after 2 years of follow-up may not require any treatment. In another subset of patients, GnRH analog therapy may be associated with a marked deceleration of bone growth that may ultimately result in an adult stature that is less than the targeted midparental height. GH may be offered to these patients in order to achieve the targeted adult height. There have been no randomized controlled trials comparing final adult height in those treated with GnRH analogs alone versus GnRH analogs combined with growth hormone therapy, and the largest case series includes 35 patients. Case series suggest that GH is most commonly offered as an adjunct to GnRH analogs when the growth velocity drops below the 25th percentile for chronological age. (16, 17) A series of comparative case series that have included final adult heights have been reported by the same group of investigators from Italy. This group of investigators is the only one to have reported final adult heights. The most recent reports focus on a group of 17 girls with precocious puberty and a growth velocity below the 25th percentile who were treated with a combination of GnRH and GH, and 18 girls who refused treatment with adjunctive GH. (17) Those in the combined group attained a significantly greater adult height (161.2 +/- 4.8 cm) than the “control” group (156.7 +/- 5.7 cm) This small study is inadequate to permit scientific conclusions. Tuvemo and colleagues reported on the results of a trial that randomized 46 girls with precocious puberty to receive either GnRH analogs or GnRH analogs in addition to GH. (18) Of interest, all the participants were adopted from developing countries; precocious puberty is thought to be common in such cross cultural adoptions. Criteria for participation in this trial did not include predicted adult height or growth velocity. After 2 years of treatment, the mean growth and predicted adult height were greater in those receiving combined treatment compared to those receiving GnRH analogs alone. The absence of final height data limits interpretation of this trial.

As noted above, the “not medically necessary” status of other applications of GH for non-GH deficient short-stature children is based on the absence of a functional impairment associated with a less than predicted final adult height. While these same considerations may apply to using GH therapy as a component of therapy for precocious puberty, the “investigational” status of this indication is based on lack of final height data from controlled trials.

As noted above, the “not medically necessary” status of other applications of GH for non-GH deficient short-stature children is based on the absence of a functional impairment associated with a less than predicted final adult height. While these same considerations may apply to using GH therapy as a component of therapy for precocious puberty, the “investigational” status of this indication is based on lack of final height data from controlled trials.

GH Therapy in Older Adults without Documented Growth Hormone Deficiency

 

The GH secretion rate decreases by an estimated 14% per decade after young adulthood; mean levels in older adults are less than half those of a young adult. However, mean GH levels in older adults are greater than age-matched adults with diagnosed GH deficiency. Older individuals experience changes in body composition, loss of muscle mass, and decreases in bone mineral density that are similar to changes seen in adults with biochemically verified GH deficiency. Based on these observations, GH therapy has been investigated in older adults without organic pituitary disease. The policy regarding this off-label application is based on a 2001 TEC Assessment (19), which offered the following observations and conclusions:

• In 2003, the AACE updated their published clinical guidelines regarding GH use (20). Regarding the use of GH in adults, the AACE guidelines noted that “there is no place for the use of GH as an antiaging agent . . . [this use] should remain in experimental categories.”
• Only 8 small controlled trials with at least 10 patients per treatment arm have examined the effect of GH therapy on older patients who may have partial GH deficiency. Overall, these trials reported improved bone density,increased lean body mass, and decreased fat massin rhGH-treated versus control arms. However, results were not statistically significant and consistent across trials. Information on physical performance and quality of life outcomes was insufficient to draw conclusions regarding functional and long-term benefits from rhGH treatment.In 3 of 6 trials, noticeably fewer patients were evaluable in the treated than in the control arms. All trials used starting rhGH doses that were above the currently recommended range.
• It is not possible to prove effectiveness of GH treatment or lack thereof unless otherwise similar groups of treated versus non-treated patients are compared over a sufficient length of time to allow detection of any significantly and clinically different results. Currently limited results do not document clinically significant benefits with rhGH therapy, and they have potential for bias. The available evidence is insufficient to determine whether rhGH improves health outcomes in adults with age-related GH deficiency.

GH Therapy as a Treatment of Altered Body Habitus Related to Antiretroviral Therapy for HIV Infection

 

There has been research interest in the use of GH to treat the altered body habitus that may be a complication of antiretroviral therapy for HIV infection. Body habitus changes, also referred to as the fat redistribution syndrome, include thinning of the face, thinning of the extremities, truncal obesity, breast enlargement, or an increased dorsocervical fat pad ("buffalo hump"). (21) However, there is minimal published literature regarding the use of GH for this indication. The literature is dominated by letters to the editors and small case series. The largest case series was reported by Wanke and colleagues who treated 10 HIV-infected patients with fat redistribution syndrome with GH for 3 months. (22) The authors reported improved waist/hip ratio and mid-thigh circumference.

GH Therapy for Severe Burns

 

Mortality was studied in a controlled trial of 54 adult burn patients who survived the first 7 post-burn days (23). Those patients showing difficulty with wound healing were treated with rhGH and compared to those healing at the expected rate with standard therapy. Mortality of rhGH treated patients was 11% compared to 37% not receiving rhGH (p=0.027). Infection rates were similar in both groups. In a randomized, double-blind, placebo-controlled trial of 40 severely burned children, the length of hospital stay was reduced from a mean of 0.8 days per % total body surface area (TBSA) burned for the placebo group to 0.54 days per % TBSA burned for the treatment group (p less than 0.05) (24). For the average 60% TBSA-burned patient, this approximates a length of stay reduction from 46 to 32 days. Singh et al (25) studied 2 groups of patients ('n=22) with comparable third-degree burns; those who received GH had improved wound healing and lower mortality (8% vs. 44%). Demling et al (26) found significantly improved weight retention and wound healing time with GH or oxandrolone compared to standard treatment in 36 adults with severe burns.

 

Two phase III double-blind randomized controlled trials of GH treatment in adults following cardiac or abdominal surgery, multiple trauma, or acute respiratory failure found increased in-hospital mortality rates in patients who received GH (27). The potential for increased mortality prompted additional studies in critically burned pediatric patients. Ramirez et al. (28) retrospectively studied 263 pediatric burn patients; those treated with GH had no increase in mortality from matched patients who did not receive GH.

 

However, a randomized, controlled trial in 56 children with more than 40% total body surface area burns found no benefit of GH alone compared to or in combination with propanolol (29). Another placebo-controlled trial (30) found no benefit to GH with regard to length of hospitalization in 24 adult patients with severe burns.

GH Therapy to Prevent Growth Delay in Children with Severe Burns

 

Children with severe burns show significant growth delays for up to 3 years after injury. GH treatment in 72 severely burned children for 1 year after discharge from intensive care resulted in significantly increased height in a placebo-controlled, randomized, double-blinded trial (31). Aili Low et al (32) found that GH treatment in severely burned children during hospitalization resulted in significantly greater height velocity during the first 2 years after burn compared to a similar group of untreated children.

GH Therapy in Conjunction with Optimal Management of Short Bowel Syndrome.

 

Short bowel syndrome is experienced by patients who have had half or more of the small intestine removed with resulting malnourishment because the remaining small intestine is unable to absorb enough water, vitamins, and other nutrients from food. The FDA label for Zorbtive indicates growth hormone has been shown in human clinical trials to enhance the transmucosal transport of water, electrolytes, and nutrients. The FDA approval for Zorbtive was based on the results of a randomized, controlled, phase III clinical trial in which patients dependent on intravenous parenteral nutrition who received Zorbtive (either with or without glutamine) over a 4-week period had significantly greater reductions in the weekly total volume of intravenous parenteral nutrition required for nutritional support. However, the effects beyond 4 weeks were not evaluated nor were the treatment location (inpatient vs. outpatient) identified. Several published studies have also demonstrated improved intestinal absorption in short bowel syndrome patients receiving parenteral nutrition. (33-35) However, studies have noted the effects of increased intestinal absorption are limited to the treatment period. (33, 34, 36) Specialized clinics may offer intestinal rehabilitation for patients with short bowel syndrome; GH may be one component of this therapy. Inpatient intestinal rehabilitation is considered separately in policy No. 2.01.48.

Other Indications

 

GH therapy has been investigated for use in the treatment of cystic fibrosis, idiopathic dilated cardiomyopathy, and juvenile idiopathic arthritis. (37-41) No randomized clinical trials were identified to sufficiently demonstrate the appropriateness of GH therapy in these conditions.

2006 Update

 

A literature review update for the period of May 2004 through July 2006 identified no published clinical trials to alter the conclusions reached above. Ding and colleagues randomized 48 patients with chronic severe hepatitis B to evaluate growth hormone with lactulose versus no growth hormone. (42) The authors noted clinical improvement in 90% of patients; however, this study focused on intermediate short-term outcomes and no conclusions can be drawn from the study. Therefore, chronic infectious disease is added to the investigational policy statement on anabolic therapy for catabolic illness.

June 2008 Update
The policy was updated on three topics: Prader-Willi syndrome, Noonan syndrome, and cystic fibrosis, in June 2008 using a literature search through MEDLINE.
Prader-Willi Syndrome
Use of human growth hormone for patients with growth failure due to Prader-Willi syndrome is an FDA-approved indication. Most patients with this syndrome have hypothalamic dysfunction and growth hormone deficiency. Numerous studies have shown patient improvements with use of growth hormone. For example, a recent randomized study reported by Festen involving 42 infants and 49 children, showed growth hormone-treatment significantly improved height, BMI, head circumference, and body composition. (43) Recently deaths have been reported in Prader-Willi patients who are being treated with growth hormone. (44) A number of these deaths occurred in children with morbid obesity, respiratory or sleep disorders. Airway obstruction has been hypothesized as a potential cause; however, the exact role of growth hormone is not certain. Because of this, many specialists now recommend sleep studies and correction of underlying airway obstruction before initiating growth hormone treatment in these patients.
Questions have been raised about the value of testing for growth hormone deficiency before treatment in these patients. The majority of patients with Prader-Willi syndrome (PWS) are growth hormone (GH) deficient. A number of recent clinical studies on use of GH in PWS were reviewed. In none of these studies were patients selected for treatment based on presence or absence of growth hormone nor were results reported separately for those with or without GH deficiency (and thus no differential impact was noted.) One older study did describe a series of PWS patients treated with GH that were GH-deficient. (45) However, the FDA-approval is for those with PWS and growth-failure, thus this “growth-failure” indication is added to the policy statement.
Noonan Syndrome
In 2007, the FDA approved use of growth hormone (Norditropin) for treatment of short stature in children with Noonan Syndrome. This approval was based on a comparative study of 21 children that showed improvement in height and growth velocity in those with short stature due to Noonan Syndrome. (46)
Cystic Fibrosis
Since use of human growth hormone is not an FDA-approved for this indication, this use is considered investigational. This policy statement is unchanged. However, some studies have shown improvement in height and weight during GH treatment of patients with cystic fibrosis. (44)

 

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3. Finkelstein BS, Imperiale TF, Speroff T et al. Effect of growth hormone therapy on height in children with idiopathic short stature: a meta-analysis. Arch Pediatr Adolesc Med 2002; 156(3):230-40.
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7. Genotropin, Package Insert
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11. Humatrope, package insert
12. Nutropin, package insert
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14. Walvoord EC, Pescovitz OH. Combined use of growth hormone and gonadotropin-releasing hormone analogues in precocious puberty: theoretic and practical considerations. Pediatrics 1999; 104(4 pt 2):1010-4.
15. Manasco PK, Pescovitz OH, Hill SC et al. Six-year results of luteinizing hormone releasing hormone (LHRH) agonist treatment in children with LHRH-dependent precocious puberty. J Pediatr 1989; 115(1):105-8.
16. Tato L, Saggese G, Cavallo L et al. Use of combined Gn-RH agonist and hGH therapy for better attaining the goals in precocious puberty treatment. Horm Res 1995; 44(suppl 3):49-54.
17. Pucarelli I, Segni M, Ortore M et al. Effects of combined gonadotropin-releasing hormone agonist and growth hormone therapy on adult height in precocious puberty: a further contribution. J Pediatr Endocrinol Metab 2003; 16(7):1005-10.
18. Tuvemo T, Gustafsson J, Proos LA. Growth hormone treatment during suppression of early puberty in adopted girls. Acta Paediatr 1999; 88(9):928-32.
19. 2001 TEC Assessment; Tab 11: Recombinant Human Growth Hormone (GH) Therapy in Adults with Age-Related GH Deficiency.
20. AACE Growth Hormone Task Force. American Association of Clinical Endocrinologists medical guidelines for hormone use in adults and children—2003 update. Endocrine Practice 2003; 9(1):65-76.
21. Lo JC, Mulligan K, Tai VW et al. “Buffalo hump” in men with HIV-1 infection. Lancet 1998; 351(9106):867-74.
22. Wanke C, Gerrior J, Kantaros J et al. Recombinant human growth hormone improves the fat redistribution syndrome (lipodystrophy) in patients with HIV. AIDS 1999; 13(15):2099-13.
23. Knox J, Demling R, Wilmore D et al. Increased survival after major thermal injury: the effect of growth hormone therapy in adults. J Trauma 1995; 39(3):526-30.
24. Herndon DN, Barrow RE, Kunkel KR et al. Effect of recombinant human growth hormone on donor-site healing in severely burned children. Ann Surg 1990; 212(4):424-9.
25. Singh KP, Prasad R, Chari PS et al. Effect of growth hormone therapy in burn patients on conservative treatment. Burns 1998; 24(8):733-8.
26. Demling RH. Comparison of the anabolic effects and complications of human growth hormone and the testosterone analog, oxandrolone, after severe burn injury. Burns 1999; 25(3):215-21.
27. Takala J, Ruokonen E, Webster NR et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med 1999; 341(11):785-92.
28. Ramirez RJ, Wolf SE, Barrow RE et al. Growth hormone treatment in pediatric burns: a safe therapeutic approach. Ann Surg 1998; 228(4):439-48.
29. Hart DW, Wolf SE, Chinkes DL et al. Beta-blockade and growth hormone after burn. Ann Surg 2002; 236(4):450-6.
30. Losada F, Garcia-Luna PP, Gomez-Cia T et al. Effects of human recombinant growth hormone on donor-site healing in burned adults. World J Surg 2002; 26(1):2-8.
31. Hart DW, Herndon DN, Klein G et al. Attenuation of posttraumatic muscle catabolism and osteopenia by long-term growth hormone therapy. Ann Surg 2001; 233(6):827-34.
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43. J. Clin Endocronology Metabolic 87: 2067 - 2079, 2002.
44. Festen DA, de Lind van Wijngaarden R, van Eekelen M et al. Randomized controlled growth hormone trial: Effects on anthropometry, body composition, and body proportions in a large group of children with Prader-Willi syndrome. Clin Endocrinol 2008 Mar 18 (Epub ahead of print)
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46. Lindgren AC, Hagenas L, Muller J et al. Effects of growth hormone treatment on growth and body composition in Prader-Willi syndrome: a preliminary report. The Swedish National Growth Hormone Advisory Group. Acta Paediatr Suppl 1997; 423:60-2.
47. FDA approval. Accessed at www.fda.gov/cder/foi/label/2007/021148s016lbl.pdf

Index

Policy History

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