14.1 Treatment of SBS in Adults
Study 1 (Placebo-controlled) and Study 2 (Open-label Extension of Study 1)
Study 1 (CL0600-020, NCT00798967)
The efficacy, safety, and tolerability of GATTEX was evaluated in a randomized, double-blind, placebo-controlled, parallel-group, multi-national, multicenter clinical study (Study 1) in adults with SBS who were dependent on parenteral nutrition/intravenous (PN/I.V.) support for at least 12 months and required PN at least 3 times per week. For 8 weeks (or less) prior to randomization, investigators optimized the PN/I.V. volume of all patients. Optimization was followed by a 4-week to 8-week period of fluid stabilization. Patients then were randomized (1:1) to placebo (n=43) or GATTEX 0.05 mg/kg/day (n=43). Study treatment was administered subcutaneously once daily for 24 weeks. PN/I.V. volume adjustments (up to 30% decrease) and clinical assessments were made at 2, 4, 8, 12, 20, and 24 weeks.
The primary efficacy endpoint was based on a clinical response, defined as a patient achieving at least 20% reduction in weekly PN/I.V. volume from Baseline (immediately before randomization) to both Weeks 20 and 24.
The mean age of patients was 50 years. Mean duration of PN/I.V. dependency prior to enrollment was 6 years (range 1 to 26 years). The most common reasons for intestinal resection leading to SBS were vascular disease (34%, 29/85), Crohn’s Disease (21%, 18/85), and “other” (21%, 18/85). Stoma was present in 45% (38/85) of patients, and the most common type was jejunostomy/ileostomy (82%, 31/38). The mean length of remaining small intestine was 77.3±64.4 cm (range: 5 to 343 cm). The colon was not in continuity in 44% (37/85) patients. At baseline, the mean
(± SD) prescribed days per week for PN/I.V. infusion was 5.73 (±1.59) days.
The percentages of treatment group responders were compared in the intent-to-treat population of this study which was defined as all randomized patients. Sixty-three percent (27/43) of GATTEX-treated patients versus 30% (13/43) of placebo-treated patients were considered responders (p=0.002).
At Week 24, the mean reduction in weekly PN/I.V. volume was 4.4 Liters for GATTEX-treated patients (from pre-treatment baseline of 12.9 Liters) versus 2.3 Liters for placebo-treated patients (from pre-treatment baseline of 13.2 Liters/week) (p<0.001).
Twenty-one patients on GATTEX (54%) versus 9 on placebo (23%) achieved at least a one-day reduction in PN/I.V. support.
The mean changes from Baseline in PN/I.V. volume by visit are shown in Figure 2.
Study 2 (CL0600-021, NCT00930644)
Study 2 was a 2-year open-label extension of Study 1 in which 88 patients received GATTEX 0.05 mg/kg/day. Ninety-seven percent (76/78) of patients who completed Study 1 elected to enroll in Study 2 (37 received GATTEX; 39 received Placebo). An additional 12 patients entered Study 2, who had been optimized and stabilized but not randomized in Study 1 because of closed enrollment.
30 months exposure
Thirty GATTEX patients completed a total duration of 30 months (Study 1 followed by Study 2 treatment). Of these, 28 patients (93%) achieved a 20% or greater reduction of parenteral support (PS). Of responders in Study 1 who had completed 2 additional years of continuous treatment with GATTEX, 96% (21/22) sustained their response to GATTEX. The mean reduction in PN/I.V. (n=30) was 7.55 L/week (a 66% reduction from baseline). Ten patients were weaned off their PN/I.V. support while on GATTEX treatment for 30 months. Patients were maintained on GATTEX even if no longer requiring PN/I.V. support. These 10 patients had required PN/I.V. support for 1.2 to 15.5 years, and prior to GATTEX had required between 3.5 L/week and 13.4 L/week of PN/I.V. support. At the end of study, 21 (70%), 18 (60%) and 18 (60%) of the 30 completers achieved a reduction of 1, 2, or 3 days per week in PN/I.V. support, respectively.
24 months exposure
Of the 39 placebo-treated patients from Study 1 entering Study 2, 29 completed 24 months of treatment with GATTEX. The mean reduction in PN/I.V. was 3.11 L/week (an additional 28.3% reduction) from the start of Study 2. Sixteen (55%) of the 29 completers achieved a 20% or greater reduction of PS. At the end of the study, 14 (48%), 7 (24%) and 5 (17%) achieved a reduction of 1, 2, or 3 days per week in PN/I.V. support, respectively. Two patients were weaned off their PN/I.V. support while on GATTEX. Of the 12 patients entering Study 2 directly, 6 completed 24 months of treatment with GATTEX. Similar effects were seen. One of the six patients was weaned off their PN/I.V. support while on GATTEX.
Study 3 (Placebo-controlled) and Study 4 (Blinded Uncontrolled Extension of Study 3)
Study 3 (CL0600-004, NCT00081458)
Study 3 was a randomized, double-blind, placebo-controlled, three parallel-group, multinational study in adults with SBS who were dependent on parenteral nutrition/intravenous (PN/I.V.) support for at least 12 months and required PN at least 3 times per week. After a period of optimization and stabilization similar to Study 1, patients were randomized to receive 24 weeks of one of the following treatment regimens: GATTEX 0.05 mg/kg/day (n=35), GATTEX 0.1 mg/kg/day (twice the recommended dose) (n=33), or placebo (n=16). GATTEX 0.1 mg/kg/day is not a recommended dosage [see Dosage and Administration (2.2)]. The treatment groups were compared using the intent-to-treat population of this study which was defined as all randomized patients who were administered at least one dose of study drug. This population contained one less patient in the 0.1 mg/kg/day dose group hence n=32 in this group for all analyses. The primary efficacy endpoint was a graded categorical score that did not achieve statistical significance for the high dose. Further evaluation of PN/I.V. volume reduction using the endpoint of response (defined as at least 20% reduction in PN/I.V. fluid from Baseline to Weeks 20 and 24) showed that 46% of patients on GATTEX 0.05 mg/kg/day responded versus 6% on placebo. Patients on GATTEX in both dose groups experienced a 2.5 L/week reduction in PS requirements versus 0.9 L/week for placebo at 24 weeks. Two patients in the GATTEX 0.05 mg/kg/day dose group were weaned off PS by Week 24.
Study 4 (CL0600-005, NCT00172185)
Study 4 was a blinded, uncontrolled extension of Study 3, in which 65 patients from Study 3 received GATTEX for up to an additional 28 weeks of treatment. Of responders in Study 3 who entered Study 4, 75% sustained response on GATTEX after one year of treatment. In the GATTEX 0.05 mg/kg/day dose group, a 20% or greater reduction of PS was achieved in 68% (17/25) of patients. The mean reduction of weekly PN/I.V. volume was 4.9 L/week (52% reduction from baseline) after one year of continuous GATTEX treatment. The patients who had been completely weaned off PN/I.V. support in Study 3 remained off PS through Study 4. During Study 4, an additional patient from Study 3 was weaned off PS.
14.2 Treatment of SBS in Pediatric Patients
Study 5 (TED-C14-006, NCT02682381)
Study 5 was a 24-week, multicenter study conducted in 59 pediatric patients aged 1 year through 17 years with SBS who were dependent on PS. Patients chose whether to receive GATTEX or standard of care (SOC). Patients who chose to receive GATTEX treatment were subsequently randomized in a double-blind manner to 0.025 mg/kg/day (n=24) or 0.05 mg/kg/day (n=26), while 9 patients enrolled in the SOC arm. Randomization to the GATTEX dose groups was stratified by age.
Patients treated with 0.05 mg/kg had a mean age of 6 years at baseline. The most common reasons for intestinal resection leading to SBS were gastroschisis (54%, 14/26), midgut volvulus (23%, 6/26), and necrotizing enterocolitis (12%, 3/26). Stoma was present in 19% (5/26) of patients, and the most common type was jejunostomy (80%, 4/5). The mean length of remaining small intestine was 47 (±28) cm (range: 9 to 120 cm). In the 25 patients who had remaining colon, the colon was in continuity in 22 patients. At baseline, the mean PS volume was 60 (±29) mL/kg/day (range: 24 to 133 mL/kg/day) [8 (±4) L/week (range: 3 to 19 L/week)] and mean PS infusion time was 7 (±1) days/week (range: 5 to 7 days/week) and 11 (±3) hours/day (range: 7 to 20 hours/day).
Results described in Table 3 correspond to the recommended GATTEX dosage of 0.05 mg/kg subcutaneously once daily.
Table 3: Summary of Efficacy Endpoints at Week 24* for Study 5 – Patients treated with GATTEX 0.05 mg/kg/day (N = 26)
| Efficacy Endpoints |
Results |
| Reduction in PS volume of at least 20%, n/N (%) |
18/26 (69%) |
| Achieved enteral autonomy, n/N (%) |
3/26 (12%) |
| Reduction in PS infusion of ≥1 day/week, n/N (%) |
10/26 (38%) |
| Change in PS volume from baseline (mL/kg/day), mean (SD) and [mean% (SD)] |
-23 (18) mL/kg/day [-42% (29%)] |
Study 6 (SHP633-304, NCT02954458)
Study 6 was a prospective, open-label, long-term extension study of pediatric patients who completed Study 5. In the extension study, patients received additional treatment with GATTEX 0.05 mg/kg subcutaneously once daily if they deteriorated or stopped improving after discontinuation of prior GATTEX treatment. Of the 15 patients who initially responded in Study 5 and enrolled in Study 6, 13 patients (87%) required additional treatment with GATTEX. Efficacy results at the end of the first 24-week treatment period in Study 6 (total treatment for a mean of 40 weeks) were similar to those achieved at the end of 24 weeks treatment in Study 5. One additional patient treated with 0.05 mg/kg in Study 5 eventually achieved enteral autonomy during follow-up in Study 6.
