Safety, Efficacy, and Quality of Life Improvement in Women with Prior Stress Incontinence Surgery treated with Autologous Muscle Derived Cells: Experience from Two Double-Blind, Randomized, Placebo-Controlled Trials

Dmochowski R1, Goldman H2, Lee U3, Carr L4, Peters K5, Benson K6, Thomas S7, Tu L8, Bennett J9, Heit M10, Quiroz L11, Chermansky C12, Kennelly M13, Sokol E14, Antosh D15, Wolter C16, Jankowski R17, Carlson C17, Cardello K17, Chancellor M5, Kaufman M1

Research Type

Clinical

Abstract Category

Female Stress Urinary Incontinence (SUI)

Abstract 66
Live Urogynaecology, Female & Functional Urology 2 - Management Pearls in SUI/POP/BOO
Scientific Podium Session 8
Saturday 16th October 2021
18:40 - 18:50
Live Room 1
Clinical Trial Stress Urinary Incontinence Female Stem Cells / Tissue Engineering
1. Vanderbilt University Medical Center, 2. Cleveland Clinic, 3. Benaroya Research Institute at Virginia Mason, 4. Sunnybrook Clinical Health Science Centre, 5. William Beaumont Hospital, 6. Sanford Female Pelvic Medicine and Reconstructive Surgery Clinic, 7. The American Association of Female Pelvic Medicine Specialists, 8. Centre Hospitalier Universitaire de Sherbrooke, 9. Mercy Health Saint Mary's Campus, 10. IU Health Physicians Urogynecology, 11. University of Oklahoma Health Sciences Center, 12. University of Pittsburgh Medical Center, 13. McKay Urology, 14. Stanford University, Urogynecology and Pelvic Reconstructive Surgery Clinic, 15. The Methodist Hospital Smith Tower, 16. Mayo Clinic Arizona – Mayo Clinic Hospital, 17. Cook MyoSite Incorporated
Presenter
Links

Abstract

Hypothesis / aims of study
Women with persistent or recurrent stress urinary incontinence (SUI) symptoms following anti-incontinence surgery are a challenging population due to higher safety risks and diminished efficacy from additional surgical procedures [1].  Additionally, these women reported more leaks and worse QOL at baseline in investigational studies of Autologous Muscle Derived Cells (AMDC) compared with women without prior surgery [2].  In 2020, the FDA granted Regenerative Medicine Advanced Therapy (RMAT) designation to AMDC which acknowledges that this complicated SUI sub-population meets the definition of a serious condition with unmet medical need.

Therefore, we examined if AMDC treatment for SUI is effective and improves QOL in women with persistent or recurrent SUI and a history of prior anti-incontinence surgery.
Study design, materials and methods
Preliminary data are reported from post-hoc analyses of a pooled subset of women with history of ≥1 prior surgeries for SUI >6 months prior to enrollment in 2 individual Phase 3 investigational studies of AMDC (UIAD, N=17 and IND2, N=75).  All subjects had either a prior sling surgery and/or a bladder neck suspension.  Women ≥18 years with primary symptoms of SUI and ≥3 SUI episodes over a 3-day period at screening were randomized 2:1 (AMDC:placebo) at 25 sites.  

The AMDC investigational product was manufactured from 50-250mg of skeletal muscle harvested in clinic from the subject’s vastus lateralis via biopsy, expanded to 150 million (±20%) cells, and delivered into the urinary sphincter using the Cook® Multi-Injection Needle during a subsequent clinic procedure.  Subjects were followed 2 days and 1, 3, 6, 12, and 24 months post-injection. Stress incontinence episode frequency (SIEF) was measured using 3-day bladder diary, and QOL and symptom severity were measured using validated, subject questionnaires (I-QOL, IIQ-7, GQOL, UDI-6, and ISI).  The primary outcome measure was SIEF at 12 months. Responders were defined as subjects with ≥75% reduction in SIEF at 12 months.  The incidence of product-related serious adverse events (SAEs) and product-related, injection and biopsy procedure-related adverse events (AEs) were assessed.  AEs were considered related if assessed by the Investigator as possibly, probably, or definitely related to the product/procedure. 

Investigators and subjects remained blinded through the 12-month visit. After unblinding, subjects who received placebo could elect to receive open-label AMDC treatment.  These subjects and those originally randomized to AMDC were followed for 2 years after initial blinded treatment.
Results
92 women (61 AMDC, 31 placebo) were included in this subset analysis.  At baseline, women were 58.1±11.8 years old, experienced 1.7±0.8 surgeries, 18.7±13.4 SUI episodes over 3 days, and recorded 61.8±88.6 g leakage during 24-hour pad test (mean±standard deviation). All women completed the blinded 12-month visit.  AMDC treatment effect of ≥75% SIEF reduction at 12 months was significant when compared with placebo in the pooled analysis from the UIAD and IND2 studies (44.3% vs. 16.1%; p=0.007, power=0.8, Figure 1), and independently in IND2 (40.0% vs. 16.0%; p=0.037).  The association across all subjects at 12 months exceeded a clinically meaningful threshold of ≥10-point improvement in I-QOL total score at ≥75% reduction in SIEF (Figure 2) [3].  In addition, there was significant correlation between change in SIEF and change in all QOL and symptom severity scores in AMDC subjects at 12 months (p≤0.009).  Significant differences in mean QOL and symptom severity score changes at 12 months were observed between SIEF responders and non-responders in the AMDC group but not in the placebo group in all 5 scores (p<0.01). 

Twenty-four-month diaries were completed by 73.8% (45/61) of the subjects who received AMDC. Only subjects with completed 24-month 3-day diaries were included in the durability assessment (N=45).  Treatment durability, determined as the percentage of SIEF responders at 12-months who maintained this effect at 24-months, was observed in 66.7% (16/24) of subjects (mean SIE change 0.1±0.9 between 12 and 24 months).  Additionally, 14.3% (3/21) of subjects who were non-responders at 12-months became responders by the 24-month visit.

After unblinding, 90% (28/31) of placebo subjects elected to receive open-label AMDC, 100% (28/28) of these subjects completed the 24-month final study visit and 39.3% (11/28) achieved SIEF responder status at 24 months (mean change in SIE -7.9±7.0 between 12 and 24 months).  Of these 11 responders at 24-months, 7 (63.6%) were new responders (i.e., were non-responders at 12-months).  This open-label crossover responder rate was similar to that observed in AMDC subjects at the 12-month blinded visit (Figure 1).

AMDC was well tolerated with no AMDC-related SAEs. During the blinded treatment period, the rates of subjects with any AE related to AMDC/placebo or injection procedure between groups were similar. Dysuria was the most frequently reported AE related to AMDC (3.1%) or placebo (5.8%).  The most frequently reported injection procedure-related AEs during the blinded period were injection site pain (7.7% AMDC, 0% placebo), dysuria (4.6% AMDC, 5.9% placebo), and urinary tract infection (4.6% AMDC, 5.9% placebo).  There were 3 subjects who reported urinary retention, one following placebo injection which required catheterization and resolved in 2 days, and 2 following open-label AMDC injection which did not require catheterization.  One subject experienced a biopsy procedure-related SAE of procedural pain which required hospitalization for 2 days and resolved in 4 days.  Procedural pain, post procedural contusion, and post procedural haematoma were the most common biopsy procedure-related AEs (4.8%, 3.8%, and 2.9%, respectively).
Interpretation of results
Unlike anti-incontinence sling and suspension surgeries and bulking agent injections which all produce an immediate mechanical effect that may decrease over time, augmentation of muscle function by AMDC is not expected to be immediate due to regenerative mechanisms.  Clinical data from the UIAD and IND2 studies presented here suggest that functional integration may occur over time, as additional improvements in SUI symptoms were observed in some subjects 12+ months after AMDC administration. 

The reduction in SIEF during AMDC treatment is associated with improvement in QOL and symptom severity scores in this complex population.  In particular, SIEF responders had mean score improvement well beyond an established clinically meaningful threshold with I-QOL, the most comprehensive instrument designed to capture individuals’ perception of their SUI as a serious medical condition and its impact on ability to perform day-to-day functions [3].
Concluding message
Women with persistent or recurrent SUI following prior surgical treatment have a serious unmet medical need which substantially impacts day-to-day functioning and quality of life.  Clinical evidence from 2 double-blind, randomized, multicenter, placebo-controlled trials indicates that AMDC treatment may be safe and effective at reducing SIEF and improving QOL in these women.
Figure 1 Figure 1. Percentage of Subjects with ≥75% Decrease in SIEF by Visit in Prior Surgery Subjects in UIAD/IND2 Studies
Figure 2 Figure 2. Change in I-QOL Total Score by SIEF Response in Prior Surgery Subjects in UIAD/IND2 Studies
References
  1. Lucas MG, Eur Urol 62(6):1118-29, 2012.
  2. Kaufman MR, Neurol Urodynamic 38:S3, 2019.
  3. Patrick, DL, Urology, 53(1):71-6, 1999.
Disclosures
Funding Cook MyoSite Incorporated Clinical Trial Yes Registration Number Clinicaltrials.gov, NCT01382602 and NCT01893138; EudraCT, 2011-003599-35 and 2014-002919-41 RCT Yes Subjects Human Ethics Committee Vanderbilt University IRB, Cleveland Clinic IRB, Western Institutional Review Board, Sunnybrook Health Sciences Centre Research Ethics Board, Beaumont Research Institute Human Investigation Committee, Schulman Associates IRB, Advarra IRB, Mercy Regional IRB, Comité d'éthique de la recherche en santé chez l'humain du CHUS, University of Oklahoma IRB, Copernicus Group, Research Compliance Office Stanford University, The Houston Methodist Research Institute IRB, Mayo Clinic IRB Helsinki Yes Informed Consent Yes
02/11/2024 01:06:52