Study design, materials and methods
Preliminary data are reported from a phase 1/2 study of 48 patients treated with a single administration of AMDC investigational product at a dose of 250 million (± 20%) cells. Inclusion criteria: primary symptoms of FI defined as Cleveland Clinic Incontinence Score (CCIS) ≥5 and failed conservative treatment. Exclusion criteria: previous major sphincter augmentation procedures or major anorectal operation leading to anal sphincter damage, presence of inflammatory bowel disease, and non-viable mucosa lining along the anal tract.
The AMDC investigational product is manufactured from approximately 50-250mg of skeletal muscle harvested from the patient’s vastus lateralis via biopsy and delivered into the anal sphincter during a subsequent outpatient procedure. The AMDC product was evenly distributed around the external anal sphincter (EAS) through 8-12 percutaneous injections parallel to the anal canal. For patients with a defined sphincter defect, approximately half of the AMDC product was injected in the region of the defect with the remaining volume evenly distributed through the remainder of the EAS.
The primary outcome was incidence of AMDC product- or procedure-related adverse events (AEs) and serious adverse events (SAEs) at 12 months post-treatment. Secondary outcomes were change in both frequency of FI episodes and days with FI episodes as recorded by a 28-day diary and change in CCIS and Fecal Incontinence Quality of Life (FIQL) questionnaires. Secondary outcomes were assessed by comparing baseline (pre-injection) parameters to those at 3, 6 and 12 months post-treatment. Anorectal manometry was used to explore changes in anal sphincter function from baseline to 12 months.
At the time of this interim analysis, 37 patients (34 female and 3 male, mean age 63 years, range 31-81) completed baseline diaries and had at least 2 FI episodes at the baseline diary. Of these, 35 completed the 3-month visit, 32 completed the 6-month visit, and 24 completed the 12-month visit. The main etiology of FI was obstetric injury in 25 patients (14 having sustained episiotomy and 13 obstetric tear) of whom 18 had sonographic sphincter defects and 7 had previous anal sphincter repair.
No product-related SAE were reported. One patient reported a product-related AE of inflammation of the injection site. There were 5 AEs related to the injection procedure including injection site discoloration, injection site inflammation, injection site pain, procedural pain, and procedural dizziness. The two most frequent AEs related to the biopsy procedure were procedural pain (12 events) and procedural contusion (5 events). All AEs related to the biopsy procedure were of low severity.
Twelve months from the injection of the AMDC product, there was a 45% reduction in median FI episodes compared to baseline (from 16 episodes to 9; Table 1). Similarly, a significant reduction in median days with FI episodes compared to baseline was observed at all time points (from 13 days to 9.5, 8 and 6.5 days at 3, 6 and 12 months respectively [p=0.03]). At the 12-month follow-up, 50% (12/24) of patients reported a ≥50% reduction in number of FI episodes, 33% (8/24) reported a ≥75% reduction in number of episodes and 21% (5/24) of patients reported zero FI episodes. Reduction in days with FI episodes at each threshold were reported in a similar percentage of patients. Symptom severity improved over the follow-up period as demonstrated by a statistically significant reduction of CCIS at 12 months compared to baseline (p<0.01). There was also a significant improvement in FIQL scales at 12 months compared to baseline (p≤0.05). Compared to baseline manometry, length in high-pressure canal zone showed a statistically significant change at 12 months with an increase in mean length from 1.8 to 2.4 cm (Table 1).
Interpretation of results
Interim data analysis of the ongoing Phase 1/2 study to evaluate safety and efficacy of the AMDC investigational product for the treatment of FI, suggests that the product is safe with only 1 reported product-related adverse reaction and few non-serious procedure-related AEs, which were of low severity and self-resolving in most cases.
The reduction in both number of FI episodes and days with FI episodes, along with significant improvements in both CCIS and FIQL observed after 12 months, demonstrates that a single administration of AMDC investigational product shows promise in improving symptoms and quality of life in patients with fecal incontinence. A 50% reduction in the number of FI episodes or days with episodes is considered a clinically important improvement in therapeutic trials of FI. In the heterogeneous patient population enrolled, we found that, overall, 50% of patients had at least a 50% reduction in both number of FI episodes and days with FI episodes. An analysis of patient demographics and medical history suggests that patients with previous history of obstetric trauma (episiotomy) or anal sphincter repair may respond best to AMDC. Respectively, 88% of patients with episiotomy and 100% with anal sphincter repair, had at least a 50% reduction in FI episodes at 12 months (in keeping with previous reports in this patient group [1,2]).