Predicate Devices

Not Found

Reference Devices

Not Found

AI/ML (Artificial Intelligence / Machine Learning)

No
The device description and performance studies focus on the physical properties and effects of the hydrogel particles in the GI tract. There is no mention of AI, ML, or any computational analysis of data for diagnosis, treatment, or prediction.

Therapeutic

Yes
Plenity is indicated to aid in weight management in adults with a Body Mass Index (BMI) of 25 - 40 kg/m², aiming to treat obesity, which is a medical condition.

Diagnostic

No

Explanation: The device, Plenity, is described as a non-systemic hydrogel for weight management that works by occupying volume in the stomach and small intestine to create a sensation of fullness. Its function is to aid in weight management, which is a therapeutic purpose, not a diagnostic one. There is no mention of it being used to detect, diagnose, or monitor a disease or condition.

SaMD (Software as a Medical Device)

No

The device description clearly states that Plenity is a porcine gelatin capsule containing hydrogel particles. This is a physical substance intended to be ingested and occupy volume in the GI tract, making it a physical medical device, not software.

IVD (In Vitro Diagnostic)

Based on the provided information, this device is not an In Vitro Diagnostic (IVD).

Here's why:

IVDs are used to examine specimens from the human body. The description of Plenity clearly states it is a capsule taken orally that works directly in the gastrointestinal tract. It is not used to test blood, urine, tissue, or any other bodily fluid or substance outside of the body to diagnose, monitor, or screen for a condition.
Plenity's mechanism of action is physical. It works by occupying volume in the stomach and small intestine to create a sensation of fullness. This is a physical interaction within the digestive system, not a diagnostic test performed on a specimen.
The intended use is weight management. While weight can be a factor in various health conditions, Plenity's purpose is to aid in weight loss through a physical mechanism, not to diagnose or monitor a disease.

Therefore, Plenity falls under the category of a medical device, but not specifically an In Vitro Diagnostic device.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

Plenity is indicated to aid in weight management in overweight and obese adults with a Body Mass Index (BMI) of 25 - 40 kg/m², when used in conjunction with diet and exercise.

Product codes

QFQ

Device Description

Plenity is a porcine gelatin capsule that contains thousands of absorbent hydrogel particles (0.75 grams [g] per capsule); each particle is approximately the size of a grain of salt (see Figure 1). Plenity is non-systemic and works directly in the gastrointestinal (GI) tract. Plenity hydrogel is made from two natural ingredients, cellulose and citric acid, that form a three-dimensional matrix designed to occupy volume in the stomach and small intestine, to create a sensation of fullness. Plenity is provided non-sterile.

The capsules disintegrate in the stomach and release the Plenity particles, which can hydrate up to 100 times their original weight. When fully hydrated, the individual non-clustering Plenity particles from the 2.25 g/dose occupy about a quarter of the average stomach volume. The gel particles mix with ingested foods, creating a larger volume with higher elasticity and viscosity in the stomach and small intestine.

Plenity passes through the digestive system, maintaining its three-dimensional structure in the stomach and small intestine before breaking down in the colon. The water is then released and reabsorbed by the body. Plenity particles are eliminated through normal bowel movements; they are not absorbed by the body.

Patients consume three (3) capsules (2.25 g/dose) with water before both lunch and dinner. Plenity is supplied in double blister packs that, together, provide the two doses patients take daily. Each individual blister pack holds a single dose of three (3) capsules. Seven (7) double blister packs are supplied in a weekly package.

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

stomach and small intestine, GI tract, digestive system, colon

Indicated Patient Age Range

adults

Intended User / Care Setting

Not Found

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Not Found

Summary of Performance Studies

Pivotal Study (GLOW)

Study type: multicenter, randomized, double-blind, sham-controlled, parallel-group study assessing the safety and efficacy of 2.25 g of Plenity on body weight over 24 weeks.
Sample size: 436 overweight and obese subjects (with and without type 2 diabetes)
Key results:
- Primary endpoints:
  - Superiority margin of 3% of the percent total body weight loss (%TBWL) for the Plenity group compared to the Sham group: The difference did not meet the pre-defined threshold of 3% and the lower limit of the CI did not surpass 3%; therefore, super-superiority had not been established. However, the difference between the Plenity and Sham groups (-6.41 ± 5.79 vs. -4.39 ± 5.52) was statistically different (p = 0.0007).
  - More than 35% of subjects on Plenity achieving at least 5% TBWL (performance goal): The percent of responders with >5% weight loss was 58.6% (95% CI: 51.8, 65.4), significantly exceeding the performance goal of 35% (p95%) adverse events were assessed by the investigator as mild or moderate in intensity. No serious adverse events (SAE) in the Plenity group, whereas there was one (1) non-device related SAE in the Sham group (colon adenoma). No deaths occurred.

Extended Study (GLOW-EX)

Study type: open-label, one arm extension study. Assessed the effect of Plenity on body weight after an additional exposure of 24 weeks.
Sample size: 18 subjects who were assigned to Sham and 21 subjects who were assigned to Plenity from the GLOW study. Of these, 17 and 18 subjects, respectively, completed the extended treatment.
Key results:
- Safety results: The overall incidence of AEs was no different between the Plenity subjects who were exposed for an entire year (29 AEs in 10 [47.6%] subjects) versus the Sham subjects who were switched to Plenity and exposed to Plenity for the first time for a period of 24 weeks (37 AEs in 12 [66.7%] subjects). No deaths and no SAEs.
- Efficacy results: Subjects treated with Plenity during GLOW (21 subjects) achieved a total of 7.9% weight loss after 48 weeks. For subjects assigned to Sham in GLOW (18 subjects) who then started Plenity, they lost an additional 2.5% ± 4.1% over the subsequent 24 weeks.

Gastric Emptying Study (IMAGES)

Study type: single center partially-blinded, randomized, four-way, crossover, two-part study. Assessed and compared the gastric emptying kinetics and gastrointestinal (GI) transit times of a radiolabeled meal following a single administration of either 2.25g or 3.75g of Plenity or Sham.
Sample size: eight overweight/obese male volunteers in each part.
Key results: No differences were observed in the rate of gastric emptying between Plenity and Sham arms of the study.

Drug-Device Interaction Study

Study type: single center, randomized, single-dose, open-label, 4-period, 4-way, crossover, device-drug interaction, performed under fasting and fed conditions. Evaluated the effect of Plenity capsules on the pharmacokinetics (PK) of metformin.
Sample size: N=24 healthy, overweight or obese subjects.
Key results: Results support that Plenity affects metformin absorption similar to food.

Key Metrics

GLOW Study - ITT-MI Analysis Population (Primary Endpoint: Percent TBWL):
- Plenity (N=223): Mean ± SD = -6.41 ± 5.79
- Sham (N=213): Mean ± SD = -4.39 ± 5.52
- LS Mean Difference: -2.07 ± 0.59 (95% CI: -3.24, -0.90)
- p-value: Superiority = 0.0007
GLOW Study - ITT-MI Analysis Population (Co-primary Endpoint: Body Weight Responders > 5% TBWL):
- Plenity (N=223): 58.6% (95% CI: 51.8, 65.3)
- Sham (N=213): 42.2% (95% CI: 35.2, 49.1)
- p-value:

Regulation Number and Section

§ 876.5982 Ingested, transient, space occupying device for weight management and/or weight loss.

(a)
Identification. This device is an ingested material that transiently occupies space in the stomach. The device passes from the body via the natural gastrointestinal tract.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The patient-contacting components of the device must be demonstrated to be biocompatible for its intended use.
(2) Non-clinical performance testing must demonstrate that the device performs as intended under anticipated conditions for use, as follows:
(i) Performance bench testing in a simulated use model must evaluate device disintegration and device hydration state throughout the gastrointestinal tract;
(ii) Bioburden and moisture content assessments must evaluate device infection risk throughout the labeled shelf life; and
(iii) Performance data must support the shelf life of the device by demonstrating continued package integrity and device functionality over the labeled shelf life.
(3) Clinical performance testing must demonstrate the device performs as intended and evaluate the following:
(i) Weight change;
(ii) All adverse events, including obstruction, dilation, diarrhea, constipation, and dehydration; and
(iii) Interaction with representative medications.
(4) Physician and patient device labeling must state:
(i) The clinical benefit of the device as assessed by using percent total body weight loss;
(ii) Treatment must be offered in combination with diet and exercise;
(iii) Instructions on how to use the device as intended including how to avoid interaction with medication; and
(iv) The shelf life of the device.

Summary

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DE NOVO CLASSIFICATION REQUEST FOR PLENITY

REGULATORY INFORMATION

FDA identifies this generic type of device as:

Ingested, transient, space occupying device for weight management and/or weight loss. This device is an ingested material that transiently occupies space in the stomach. The device passes from the body via the natural gastrointestinal tract.

NEW REGULATION NUMBER: 21 CFR 876.5982

CLASSIFICATION: Class II

PRODUCT CODE: QFQ

BACKGROUND

DEVICE NAME: Plenity

SUBMISSION NUMBER: DEN180060

DATE DE NOVO RECEIVED: November 15, 2018

SPONSOR INFORMATION:

Gelesis, Inc. 501 Boylston Street, Suite 6102 Boston, MA 02116

INDICATIONS FOR USE

Plenity is indicated to aid in weight management in overweight and obese adults with a Body Mass Index (BMI) of 25 - 40 kg/m², when used in conjunction with diet and exercise.

LIMITATIONS

The sale, distribution, and use of Plenity are restricted to prescription use in accordance with 21 CFR 801.109.

In the clinical study of the device, patients were required to use Plenity along with a weight management program of nutrition, diet, and exercise instruction.

Plenity should be taken as directed in the labeling to avoid adverse interaction with other oral medication.

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Plenity is contraindicated for use under the following conditions:

Pregnancy
History of allergic reaction to cellulose, citric acid, sodium steary] fumarate, . gelatin, or titanium oxide

PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS. PRECAUTIONS AND CONTRAINDICATIONS.

DEVICE DESCRIPTION

Plenity is a porcine gelatin capsule that contains thousands of absorbent hydrogel particles (0.75 grams [g] per capsule); each particle is approximately the size of a grain of salt (see Figure 1). Plenity is non-systemic and works directly in the gastrointestinal (GI) tract. Plenity hydrogel is made from two natural ingredients, cellulose and citric acid, that form a three-dimensional matrix designed to occupy volume in the stomach and small intestine, to create a sensation of fullness. Plenity is provided non-sterile.

Image /page/1/Picture/6 description: The image shows several empty white capsules and a pile of white powder. The capsules are open, suggesting they are ready to be filled with the powder. The powder is granular and appears to be a pharmaceutical ingredient. The scene is set on a clean, metallic surface, likely in a laboratory or pharmaceutical setting.

Figure 1. Plenity capsules with hydrogel exposed

The capsules disintegrate in the stomach and release the Plenity particles, which can hydrate up to 100 times their original weight. When fully hydrated, the individual non-clustering Plenity particles from the 2.25 g/dose occupy about a quarter of the average stomach volume. The gel particles mix with ingested foods, creating a larger volume with higher elasticity and viscosity in the stomach and small intestine.

Plenity passes through the digestive system, maintaining its three-dimensional structure in the stomach and small intestine before breaking down in the colon. The water is then released and reabsorbed by the body. Plenity particles are eliminated through normal bowel movements; they are not absorbed by the body.

Patients consume three (3) capsules (2.25 g/dose) with water before both lunch and dinner. Plenity is supplied in double blister packs that, together, provide the two doses patients take

2

daily. Each individual blister pack holds a single dose of three (3) capsules. Seven (7) double blister packs are supplied in a weekly package.

SUMMARY OF NONCLINICAL/BENCH STUDIES

Non-clinical/bench studies conducted on the Plenity device are summarized below.

BIOCOMPATIBILITY/MATERIALS

The Plenity Device is classified as mucosal membrane contacting for repeat, prolonged contact during clinical use (> 24 hours, ≤ 30 days). In accordance with ISO 10993-1, Biological evaluation of medical devices, and FDA Guidance: Use of International Standard ISO 10993-1. "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process", the following biocompatibility endpoints were assessed for the Plenity Device:

Cytotoxicity ●
Sensitization ●
Irritation
Oral Irritation
7-day Oral Systemic Toxicity ●
. 90-day Oral Toxicity
Material-Mediated Pyrogenicity ●
Mutagenicty ●
Toxicological Risk Assessment

Results support the biocompatibility of the Plenity Device.

PERFORMANCE TESTING - BENCH

The integrity and performance of the Plenity Device was evaluated with the nonclinical testing summarized in Table 1

| Test | Purpose | Method | Acceptance
Criteria | Results |
|-------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------|
| Nonclinical Performance Testing | | | | |
| Microbiology testing | Determine device
total bioburden
and assess for
specific enteric
and pathogenic
microbes to
confirm
acceptable
bioburden | Standard
microbiological
methods (ISO
4833-2(2013),
ISO 21527-
2(2008), ISO
16449-2(2010),
ISO 6579-
1(2008), ISO
6888-3(2004)) | Various microbial
levels | Pass |
| Test | Purpose | Method | Acceptance
Criteria | Results |
| Water activity | Determine the
relationship
between water
activity and
moisture content | Relative humidity
measurements
under equilibrium | None | Water activity at
(b) (4) moisture
content was
(b) (4) |
| Media Uptake Ratio
(MUR) | Determine the
hydration capacity
of the hydrogel
particles | Weight of the
hydrated
hydrogel
particles in
simulated gastric
fluid, minus the
weight of the dry
hydrogel
particles, divided
by the weight of
the dry hydrogel
particles | (b) (4) | (b) (4) |
| MUR after
disintegration | Determine the
hydration capacity
of the hydrogel
particles after
gelatin capsule
disintegrates | Weight of the
hydrated
hydrogel particles
in simulated
gastric fluid,
minus the weight
of the dry
hydrogel
particles, divided
by the weight of
the dry hydrogel
particles | (b) (4) | (b) (4) |
| In vitro simulation of
device transit
through the GI tract | Ensure that
hydrogel particles
uptake and release
fluid at the correct
times during the
digestion process | Measure MUR
and elastic
modulus across
time in simulated
gastric, intestinal,
and colonic fluid | Hydration kinetics
and capacity must
adequately
correlate with GI
environment | Results are
acceptable |
| Moisture content
determination | Ensure that
moisture content
does not
unnecessarily
promote microbial
growth | Samples are
analytically
weighed and then
dried at(b) (4) for
minutes and
then weighed
again | (b) (4) | (b) (4) |
| Elastic modulus | Demonstrate that
hydrated hydrogel
has comparable
mechanical | Swollen particles
are put on
rheometer plates
and tested for | (b) (4) | (b) (4) |
| Test | Purpose | Method | Acceptance
Criteria | Results |
| | properties to food
in the stomach | rheological
properties | | |
| Disintegration time | Verify time that it
takes for the
capsule to
disintegrate in the
stomach | Capsules are
immersed and
visually checked
at pre-defined
time points | Dissolution time $\leq$
minutes at (b) (4) | Pass |
| Particle size
distribution | Confirm particle
dimensions | Testing is
conducted by
means of
analytical sieving | (b) (4) % of particles
are between (b) (4)
$\mu$ m (un-
hydrated particles) | (b) (4) |
| Bulk (tapped)
density | Support that the
correct amount of
hydrogel can be
encapsulated | Volume of
known weight of
powder is
measured (b) (4) | Hydrogel tapped
density (b) (4)
mg/ml | (b) (4) |
| Uniform hydration
and disintegration
test | Confirm absence
of clumps in
hydrated material | Hydrate material | Uniform hydration
without clumps | Pass |
| Packaging Integrity Testing | | | | |
| Package integrity
(simulated
distribution and
shipping followed by
associated package
integrity testing) | Validate
packaging in
environmental
conditions | Environmental
conditioning done
in accordance
with ASTM
F2825:2010
(2015); simulated
distribution in
accordance with
ASTM D4169-
16, followed by
inspection and
bubble emission
testing (ASTM
D3078-02) | Intact boxes and
non-leaking blister
packs | Pass |
| Performance tests on
packaged capsules | Ensure that
capsules can
remain intact and
do not
prematurely
hydrate while in
packaging | Pre-determined
test methods | Gelatin capsules
will visually look
unchanged,
capsules will
disintegrate in no
more than (NMT)
(b) (4) min, the make
ratio of the
powder in the
capsules will be no
less than (NLT) | Pass |
| Test | Purpose | Method | Acceptance
Criteria | Results |
| | | | (b) (4) the
elastic modulus of
the powder in the
capsules will be
NLT (b) (4) the
loss of drying of
the power in the
capsules will be
NMT (b) (4) | |

Table 1: Summary of Nonclinical Studies

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4

5

SHELF LIFE

Table 2: Summary of Shelf-Life Testing

18-Month Real-Time Shelf-Life Testing
Media Uptake Ratio
(MUR)	Determine the
hydration capacity
of the hydrogel
particles	Weight of the
hydrated
hydrogel particles
in simulated
gastric fluid,
minus the weight
of the dry
hydrogel
particles, divided
by the weight of
the dry hydrogel
particles	(b) (4)	76.95 ± 0.48 g/g
MUR after
disintegration	Determine the
hydration capacity
of the hydrogel
particles after
gelatin capsule
disintegrates	Weight of the
hydrated
hydrogel particles
in simulated
gastric fluid,
minus the weight
of the dry
hydrogel
particles, divided
by the weight of
the dry hydrogel
particles	(b) (4)	73.81 ±0.79 g/g
Moisture content
determination	Ensure that
moisture content
does not promote
microbial growth	Moisture loss on
drying method	(b) (4) %	(b) (4) %
Elastic modulus	Demonstrate that
hydrated hydrogel
has comparable
mechanical	Swollen particles
are put on
rheometer plates
and tested for	(b) (4) Pa	(b) (4) Pa

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| | properties to food
in the stomach | rheological
properties | | |
|-------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------|------|
| Disintegration time | Verify time that it
takes for the
capsule to
disintegrate in the
stomach | Capsules are
immersed and
visually checked
at pre-defined
time points | Dissolution time $≤$
(b) (4) minutes at (b) (4) | Pass |
| Microbiology
testing | Confirm that
device is not
contaminated with
microbial species | Standard
microbiological
methods | Various microbial
levels | Pass |
| Package integrity
(blister pack bubble,
leak testing) | Evaluate the
packaging
integrity to ensure
that capsules
remain intact and
do not prematurely
hydrate throughout
the shelf-life | Testing done in
accordance with
ASTM D3078-02
Standard Test
Method for
Determination of
Leaks in Flexible
Packaging by
Bubble Emission | Seal intact | Pass |

SUMMARY OF CLINICAL INFORMATION

Clinical data from a pivotal study (GLOW), small extension study (GLOW-EX), gastric emptying study, and drug-device interaction study were leveraged to evaluate the safety and effectiveness of the Plenity Device.

Pivotal Study (GLOW)

The Gelesis Loss Of Weight (GLOW) trial (ClinicalTrials.gov, NCT02307279) was a multicenter, randomized, double-blind, sham-controlled, parallel-group study assessing the safety and efficacy of 2.25 g of Plenity on body weight over 24 weeks at 33 study sites (US and Europe) in 436 overweight and obese subjects (with and without type 2 diabetes). All subjects were prescribed reduced caloric intake and exercise. Enrollment included subjects ages 22-65 and with BMI 27-40 kg/m2. Those with BMI 10% weight loss from baseline to Day 171); ●

Estimated excess body weight (percent change from baseline to Day 171); ●
Waist circumference (change from baseline to Day 171);
Serum insulin (percent change from baseline to Day 171); ●
Homeostasis model assessment-insulin resistance (HOMA-IR) (percent change from ● baseline to Day 171);
Serum C-reactive protein (CRP) (change from baseline to Day 171);
Serum TC (percent change from baseline to Day 171);
Serum LDL-C (percent change from baseline to Day 171);
Serum high-density lipoprotein-cholesterol (HDL-C) (percent change from baseline to Day 171);
Serum TC/HDL-C ratio (change from baseline to Day 171);
Serum TG (percent change from baseline to Day 171);
Supine and standing SBP and DBP (change from baseline to Day 171);
Satisfaction (overall impression on Day 169); and
. Impact of weight on quality of life (IWOOL) (change from baseline to Day 171) at selected sites.

Safety endpoint

All Adverse Events (AEs) and Serious AEs (SAEs), including Adverse Device Effects . (ADEs) and Serious ADEs (SADEs)
To assess safety, the following were conducted or measured:
Full physical examination (excluding pelvic and rectal examination) ●
Supine and standing SBP and DBP .

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Supine and standing heart rate
. Hematology including hemoglobin, hematocrit, red blood cell count, reticulocyte count, white blood cell count with differential, and platelet count
Blood chemistry including plasma glucose and serum sodium, potassium, chloride, ● calcium, phosphorous, magnesium, blood urea nitrogen, creatinine, uric acid, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, total protein, albumin, total bilirubin, alkaline phosphatase, lactate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, and gamma glutamyltransferase

Study population demographics

The majority of subjects were Caucasian (369 [84.6%] subjects), obese Class I (BMI 30.0 - 34.9 kg/m²; 237 [54.3%] subjects), middle aged (48.0 ± 10.4 years, mean ± SD) and distributed fairly equally across gender (245 [56.2%] females, 191 [43.8%] males). Dyslipidemia was the most common co-morbidity (69.1% of subjects in the Plenity group: 72.3% of subjects in the Sham group). Most subjects had normal fasting plasma glucose (FPG) at baseline, some were classified as prediabetic (66 [29.6%] subjects in the Plenity group: 66 [31.0%] subjects in the Sham group), and few had type 2 diabetes (T2D) (21 [9.4%] subjects in the Plenity group; 25 [11.7%] subjects in the Sham group).

Subject disposition

A total of 904 subjects were screened in the GLOW study. Of these subjects, 436 were randomized with 223 subjects assigned to the Plenity group and 213 subjects assigned to Sham (intent-to-treat (ITT) cohort). 112 subjects failed to complete the treatment phase citing personal reasons as the most common cause for withdrawal (51 [23%] subjects in the Plenity group and 61 [29%] subjects on Sham). A total of 15 out of 436 (1.1%) subjects withdrew from the study due to adverse events (8 out of 223 [3.6%] subjects in the Plenity group and 7 out of 213 [3.3%] subjects on Sham). A total of 56 out of 436 (12.8%) subjects withdrew from the study based on lifestyle reasons or other personal choices (22 out of 223 [9.9%] subjects in the Plenity group and 34 out of 213 [16%] subjects on Sham). A total of 324 subjects (172 Plenity and 152 Sham) completed the entire treatment phase.

Safety results

Subjects who received treatment after randomization were included in the analysis of safety (n = 223 for Plenity and n = 211 for Sham). Overall, there were 540 (64.3%) mild AEs (282 in 124 [55.6%] subjects in the Plenity group and 258 in 117 [55.5%] subjects in the Sham group) and 276 (32.8%) moderate AEs (143 in 88 [39.5%] subjects in the Plenity group and 133 in 83 [39.3%] subjects in the Sham group) (Table 3). The overall incidence of treatment-emergent adverse events in the Plenity treatment group was no different than Sham (71.3% versus 70.6%, respectively) (Table 4). In both groups, most (>95%) adverse events were assessed by the investigator as mild or moderate in intensity (Table 5). There were no serious adverse events (SAE) in the Plenity group, whereas there was one (1) non-device related SAE in the Sham group (colon adenoma). There were two cases of severe abdominal distension and severe nausea for which discontinuation of the device resulted in resolution. No deaths occurred during the trial.

Table 3: Summary of adverse events by treatment group – Safety Population

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	Plenity (N=223)		Sham (N=211)
	Number Events	Number
Subjects with
Event
[% (n/N)]	Number Events	Number
Subjects with
Event
[% (n/N)]
Number of Subjects with
any AE	436	71.3%
(159/223)	404	70.6%
(149/211)
Grade 3 (Severe)	11	3.6% (8/223)	13	4.7% (10/211)
Grade 2 (Moderate)	143	39.5% (88/223)	133	39.3% (83/211)
Grade 1 (Mild)	282	55.6%
(124/223)	258	55.5%
(117/211)
Number of Subjects with
any SAE	0	0.0% (0/223)	1	0.5% (1/211)
Number of Subjects with
AEs leading to withdrawal	29	3.6% (8/223)	21	3.3% (7/211)
Death	0	0.0% (0/223)	0	0.0% (0/211)

Table 4: Summary of Treatment-Emergent Adverse Events by Severity (≥5% by SOC in Either Treatment Group) by Preferred Term, and Severity—Safety Population

	Plenity (N=223)		Sham (N=211)
	Number	Number
Subjects with
Event
[% (n/N)]	Number	Number
Subjects with
Event
[% (n/N)]
All Adverse Events	436	71.3%
(159/223)	404	70.6%
(149/211)
Gastrointestinal disorders
Abdominal distension	27	11.7%
(26/223)	14	6.6% (14/211)
Mild	20	8.5% (19/223)	12	5.7% (12/211)
Moderate	6	2.7% (6/223)	2	0.9% (2/211)
Severe	1	0.4% (1/223)	0	0.0% (0/211)
Abdominal pain	12	5.4% (12/223)	6	2.8% (6/211)
Mild	8	3.6% (8/223)	5	2.4% (5/211)
Moderate	4	1.8% (4/223)	1	0.5% (1/211)
Constipation1	13	5.4% (12/223)	11	5.2% (11/211)
Mild	10	4.0% (9/223)	6	2.8% (6/211)
Moderate	3	1.3% (3/223)	5	2.4% (5/211)
Diarrhea	31	12.6%
(28/223)	20	8.5% (18/211)
Mild	19	7.6% (17/223)	14	6.2% (13/211)
	Plenity (N=223)		Sham (N=211)
		Number		Number
		Subjects with		Subjects with
	Number	Event	Number	Event
	Events	[% (n/N)]	Events	[% (n/N)]
Moderate	12	4.9% (11/223)	5	1.9% (4/211)
Severe	0	0.0% (0/223)	1	0.5% (1/211)
Flatulence	21	8.5% (19/223)	14	5.2% (11/211)
Mild	19	8.1% (18/223)	14	5.2% (11/211)
Moderate	2	0.4% (1/223)	0	0.0% (0/211)
Infrequent bowel movements1	24	9.4% (21/223)	12	4.7% (10/211)
Mild	21	8.1% (18/223)	9	3.8% (8/211)
Moderate	3	1.3% (3/223)	3	0.9% (2/211)
Nausea	12	4.9% (11/223)	12	5.2% (11/211)
Mild	8	3.6% (8/223)	9	3.8% (8/211)
Moderate	3	0.9% (2/223)	2	0.9% (2/211)
Severe	1	0.4% (1/223)	1	0.5% (1/211)
Infections and infestations
Nasopharyngitis	31	11.7%
(26/223)	37	14.2%
(30/211)
Mild	25	9.0% (20/223)	30	10.9%
(23/211)
Moderate	6	2.7% (6/223)	7	3.3% (7/211)
Upper respiratory tract infection	9	3.6% (8/223)	14	5.7% (12/211)
Mild	8	3.1% (7/223)	14	5.7% (12/211)
Moderate	1	0.4% (1/223)	0	0.0% (0/211)
Musculoskeletal and connective
tissue disorders
Arthralgia	9	3.1% (7/223)	13	6.2% (13/211)
Mild	6	2.2% (5/223)	4	1.9% (4/211)
Moderate	3	0.9% (2/223)	7	3.3% (7/211)
Severe	0	0.0% (0/223)	2	0.9% (2/211)
Nervous system disorders
Headache	23	7.2% (16/223)	26	8.5% (18/211)
Mild	19	5.4% (12/223)	12	3.8% (8/211)
Moderate	3	1.3% (3/223)	12	3.8% (8/211)
Severe	1	0.4% (1/223)	2	0.9% (2/211)
[1] Coded by investigator verbatim terms using Medical Dictionary for Regulatory Authorities
[MedDRA] version 17.1
	Plenity (N=223)		Sham (N=211)
	Number
Events	Number
Subjects with
Event
[% (n/N)]	Number
Events	Number
Subjects with
Event
[% (n/N)]
Gastrointestinal Disorders [1]	158	37.7%
(84/223)	105	27.5%
(58/211)
Mild	119	28.3%
(63/223)	83	20.4%
(43/211)
Moderate	35	8.1% (18/223)	20	6.6% (14/211)
Severe	4	1.3% (3/223)	2	0.5% (1/211)
[1] Subjects with more than one AE are counted only once, at the worst severity.

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Table 5: Summary of Gastrointestinal AEs by Severity Deemed Possibly or Most Probably Related to Investigational Product - Safety Population

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A sub-analysis at four study sites measured vitamin A. B1, B2, B12, B6, B9, D, and E levels at baseline, Day 85, and Day 171. No significant differences were noted from baseline measurements or from the Sham group. No significant difference was observed for serum electrolytes or hematocrit in either group. No signals of altered absorption of medications were observed based on thyroid stimulating hormone levels of subjects on thyroid replacement therapy, blood pressure management while on antihypertensives, low density lipoprotein cholesterol (LDL-C) while on lipid lowering agents.

Efficacy results

The mean ± standard deviation (SD) %TBWL measured in kilogram [kg] from baseline to Day 171 for the ITT-MI population were -6.41 ± 5.79 and -4.39 ± 5.52 in the Plenity and Sham study groups, respectively. The adjusted mean ± standard error (SE) of difference in %TBWL from baseline to Day 171 (week 25) was -2.07 ± 0.59 (95% confidence interval (CI): -3.24, -0.90)

The difference did not meet the pre-defined threshold of 3% and the lower limit of the CI did not surpass 3%; therefore, super-superiority had not been established. However, while the difference in weight reduction did not meet the super-superiority threshold, the difference between the Plenity and Sham groups (-6.41 ± 5.79 vs. -4.39 ± 5.52) was statistically different (p = 0.0007). Table 6 provides the study results for the %TBWL in the ITT-MI and PP study populations. The ITT analyses could be influenced by the choice of statistical models, so the PP population analysis without statistical analysis is presented for transparency purposes.

ITT-MI Analysis Population	Plenity (N=223)	Sham (N=213)
Percent TBWL [1]
Mean ± SD	-6.41 ± 5.79	-4.39 ± 5.52
Median (min, max)	-5.80 (-26.40, 7.74)	-3.97 (-22.31, 15.90)
LS Mean Difference [2]
Mean ± SE	-2.07 ± 0.59
95% CI [3]	(-3.24, -0.90)
p-value: Super Superiority [4]	0.1193

Table 6: Percent TBWL from baseline to Day 171

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ITT-MI Analysis Population	Plenity (N=223)	Sham (N=213)
p-value: Superiority [5]	0.0007
PP Analysis Population	Plenity (N=154)	Sham (N=141)
Percent TBWL
Mean ± SD	-6.31 ± 6.01	-4.89 ± 5.40
Median (min, max)	-5.73 (-26.40, 7.74)	-4.15 (-19.25, 10.42)
Difference (95% CI)	-1.42 (-2.73, -0.10)
[1] Endpoint data imputed for 22.9% (51/223) in Plenity group and 28.6% (61/213) in Sham group.

[2] Difference in adjusted means taken for comparability between the two groups.

[3] 95% Confidence Interval for the difference in LS means.

[4] p-value from ANCOVA model adjusted for stratification factors and baseline weight, testing for super superiority (> 3% difference).

[5] p-value from ANCOVA model adjusted for stratification factors and baseline weight, testing for superiority (difference > 0).

Of the 436 randomized subjects, 245 of them were from European study sites and 191 from US study sites. A pooling analysis of the pivotal study was done for treatment difference on the mean of the co-primary endpoint of percent TBWL in the ITT-MI population. The unadjusted difference in treatment mean (treatment - control) and the 95% CI of this difference is -2.39% (-3.94%, -0.84%) and -1.50% (-3.16%, 0.16%) for the European pooled region and the US pooled region respectively.

The co-primary endpoint of body weight responders was successfully achieved. The percent of responders with >5% weight loss was 58.6% (95% CI: 51.8. 65.4), significantly exceeding the performance goal of 35% (p 5% TBWL from baseline to Day 171

[1] Endpoint data imputed for 22.9% (51/223) in Plenity group and 28.6% (61/213) in Sham group.

[2] Body weight responders defined as patients with ≥5% reduction in body weight.

[3] p-value from binomial proportion test for % of responders in treatment group compared to 35% performance goal.

A tipping point analysis was conducted for the performance goal of 5% weight loss and the 35% responder analysis. If all 51 missing values in the Plenity group were failures, there would be 100 (44.8%) 5% responders (95% CI: 38.2, 51.6). With all missing values set to failures, the study would have still shown success against the performance goal of 35%.

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The first secondary effectiveness endpoint did not achieve statistical significance. Since the first secondary endpoint did not achieve p