Evaluation of GERDOFF Efficacy in Combination With Proton Pump Inhibitor

Evaluation of the Effects of GERDOFF in Combination With a 6-week Therapy Based on Proton Pump Inhibitors Versus Proton Pump Inhibitors Alone on GERD-high Symptoms in Patients With Primary Diagnosis of Gastroesophageal Reflux Disease.

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03793556

Enrollment

Registered

2019-01-04

Start date

2017-05-05

Completion date

2018-12-11

Last updated

2020-03-31

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Gastro-oesophageal Reflux Disease

Brief summary

The aim of the present study was to evaluate the effect of a 6-weeks treatment of a CE-marked combination oral formulation of hyaluronic acid with chondroitin sulphate and aluminium hydroxide (GERDOFF®), in addition to proton pump inhibitors (PPI) at the standard dose, versus PPI only, in patients with first diagnosed clinical presentation of extra-esophageal GERD symptoms. The investigators verified the reduction of symptoms frequency, using a Likert questionnaire, and severity, using the Reflux Symptom Index (RSI) questionnaire, to evaluate the proportion of Responders and Non-Responder patients in these two groups after 6 weeks of treatment, compared to baseline. Moreover investigators evaluated the persistence of effects of GERDOFF® + PPI treatment on extraesophageal symptoms, after a 12-weeks follow up, only in responder patients.

Detailed description

Cough, hoarseness, prolonged voice lowering, and vocal timbre modification, without any documentable cause, are considered as minor disorders for which patients do not receive adequate attention. These disorders may represent extra-esophageal manifestations of gastro-oesophagea reflux. Accurate diagnosis and gastro-oesophageal reflux therapy have been proved as useful to improve patients' quality of life. The aim of the present study was to evaluate, in first diagnosed patients presenting with upper symptoms associated with GERD, the effect of a 6-week treatment with a combination based on CS, HA and aluminium hydroxide (Gerdoff®), co-administered with a treatment with PPIs, compared to treatment with PPIs as monotherapy, i.e. to verify, in patients treated with the combination of the two products, the reduction in symptoms frequency by means of a Likert questionnaire and the severity of upper symptoms by means of the Reflux Symptom Index (RSI) questionnaire, and to collect safety data. After 6 weeks of treatment, patients included in the two groups were then classified as responders or non-responders. Responder patients were defined as those patients that, at the 6th week of treatment, reached a RSI score decreased for at least 50% compared to baseline and an absolute value \< 13. Furthermore, the maintenance of the effect of treatment on the extra-oesophageal symptoms was evaluated after a period of follow-up lasting 12 weeks, which could be entered only by responder patients randomised in the Gerdoff®-PPI arm. Patients included in the follow-up period were randomised to receive Gerdoff® or no treatment (control group). Safety data were also evaluated in the group of patients that continued in the follow-up period.

Interventions

DEVICEGERDOFF® + Omeprazole

GERDOFF® Hyaluronic acid + chondroitin sulphate + hydroxide aluminium Melt-in-mouth tablet 1100 mg + Omeprazole was orally administered once a day before breakfast (2 capsules). The treatment lasted 6 weeks (+/- 2 days).

DRUGOmeprazole

Omeprazole, 2 capsules 20 mg, once a day before breakfast

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

Patients was randomized in an open-label treatment (in a ratio 1:1) and treated with the investigational medical device (IMD) + proton pump inhibitor (PPI) or PPI only for 6 weeks. At the end of treatment visit (V4) only patients who were classified as responders and belonging to the GERDOFF®+PPI group were included in the follow-up phase for 12 further weeks. During the follow-up, patients were randomized to an open-label treatment (in a 1:1 ratio) to GERDOFF® group or control group that will not receive any treatment for 12 weeks in order to evaluate the maintenance of treatment effects. To safeguard the health and well-being of patients, and to keep under control the possible upper symptoms of GERD that could appear, all patients that continued in the follow-up period received omeprazole as rescue medication, in a quantity adequate to cover the entire follow-up period.

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

1. Male or female subjects aged ≥ 18 years; 2. First diagnosis of GERD with upper symptoms, made on a clinical basis and confirmed by an ENT and/or confirmed by a Gastroenterologist using a RSI questionnaire; 3. Presence of extra-oesophageal symptoms associated with GERD; 4. RSI score ≥ 20; 5. Patients not pre-treated with PPIs, even for problems different from GERD, and/or with medical devices and/or similar products (e.g. antacid alginates etc..) in the last 4 weeks; 6. Cooperative patients, able to understand and adhere to the study procedures; 7. Patient able to freely give their written informed consent to study participation; 8. Patients that freely gave the consent to management of personal data related to the study.

Exclusion criteria

1. Known infective oesophagitis or oesophagitis due to acid or alkaline substances; 2. Acute or chronic rhinosinusitis; 3. Chronic bronchitis; 4. Known Zollinger-Ellison syndrome, hiatal hernia greater than 3 cm and Barrett oesophagus; 5. Ongoing neoplasias; 6. Uncontrolled diabetes; 7. Patients with impaired liver function; 8. Patients with rare hereditary problems of galactose intolerance; 9. Patients that, based on Investigator's opinion, could not take part in the study due to other diseases or concomitant therapies, such as the intake of atazanavir, nelfinavir, clopidogrel, posaconazole and erlotinib (as recommended in the Summary of Product Characteristics of Gerdoff®); 10. Patients with deficiency of Lapp lactase; 11. Patients with syndrome of glu-gal malabsorption; 12. Patients with hypersensitivity to omeprazole, substitute benzymidazolic or any of the excipients; 13. Patients already in treatment with PPIs or similar products; 14. Chronic use of drugs that interfere with the salivary secretion (e.g. anti-histamines or inhaled steroids); 15. Abuse of drug or alcohol; 16. Inability of the subject to adequately express his/her disturbances; 17. Patients with planned or ascertained pregnancy or that did not adopt an accepted contraceptive method; 18. Lactating patients.

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline to Visit V4 of the Total Score of RSI Questionnaire	In the first visit (baseline) and in the visit 4 (after 6 weeks of treatment)	After 6 weeks of treatment, the changes from baseline in the score of Reflux Symptom Index questionnaire were evaluated to verify the effects of treatments on high symptoms. The RSI questionnaire examines 9 items that are scored from 0 to 5, with a higher score that indicates a higher severity of the symptom (range of total score: 0-45).

Secondary

Measure	Time frame	Description
Total Score of Reflux Symptom Index Questionnaire in All Time-points Assessed	In baseline Visit, Visit 2 (after 1 week), Visit 3 (after 3 weeks) and Visit 4 (after 6 weeks of treatment)	Total score of the Reflux Symptom Index questionnaire assessed in all time-points. The RSI questionnaire examines 9 items, that are scored from 0 to 5, with a higher score that indicates a higher severity of the symptom (range of total score: 0-45).
Score of Hoarseness or Vocal Problem of the RSI Questionnaire Measured at the Baseline and in the Visit 4	At baseline and in the visit 4, after 6 weeks of treatment	The Reflux Symptom Index questionnaire examines 9 items, including hoarseness or vocal problem that is score from 0 to 5, with a higher score that indicates a higher severity of the symptom.
Score of Throat of the RSI Questionnarie Measured at the Baseline and in the Visit 4 of the RSI Questionnaire Score of Throat Clearance	At baseline and in the visit 4, after 6 weeks of treatment	The Reflux Symptom Index questionnaire examines 9 items, including throat that is score from 0 to 5, with a higher score that indicates a higher severity of the symptom.
Score of Excess of Mucus in the Throat or Retrosternal Fall of Secretions of the RSI Questionnaire Measured at Baseline and in the Visit 4	At baseline and in the visit 4, after 6 weeks of treatment	The Reflux Symptom Index questionnaire examines 9 items, including excess of mucus in the throat or retrosternal fall of secretions that is score from 0 to 5, with a higher score that indicates a higher severity of the symptom.
Score of Difficulty in Swallowing Food, Fluids or Pills of the RSI Questionnaire Measured at Baseline and in the Visit 4	At baseline and in the visit 4, after 6 weeks of treatment	The Reflux Symptom Index questionnaire examines 9 items, including difficulty in swallowing food, fluids or pills that is score from 0 to 5, with a higher score that indicates a higher severity of the symptom.
Score of Cough of the RSI Questionnaire Measured at Baseline and in the Visit 4 After the Meal or After Lying	At baseline and in the visit 4, after 6 weeks of treatment	The Reflux Symptom Index questionnaire examines 9 items, including cough that is score from 0 to 5, with a higher score that indicates a higher severity of the symptom.
Score of Difficulty in Breathing or Episodes of Choking of the RSI Questionnaire Measured at Baseline and in the Visit 4	At baseline and in the visit 4, after 6 weeks of treatment	The Reflux Symptom Index questionnaire examines 9 items, including difficulty in breathing or episodes of choking that is score from 0 to 5, with a higher score that indicates a higher severity of the symptom.
Score of Problematic or Troublesome Cough of the RSI Questionnaire Measured at Baseline and in the Visit 4	At baseline and in the visit 4, after 6 weeks of treatment	The Reflux Symptom Index questionnaire examines 9 items, including problematic or troublesome cough that is score from 0 to 5, with a higher score that indicates a higher severity of the symptom.
Number of Responders V6	In the Visit 6 at the end of follow-up	Responder patients of Group Gerdoff® + omeprazole were randomly assigned to receive a treatment with Gerdoff®-one tablet three times daily- All patients received a packaging of omeprazole, to be taken only if necessary, at constant dose and according to the indications of the Investigator. The scheduled duration of the follow-up period was 12 weeks. A responder was defined as a patient who at the 6th week of treatment showed a reduction of at least 50% vs. the baseline and an absolute value \< 13 on the RSI questionnaire.
Score of Stomach Burning, Thoracic Pain, Poor Digestion of Gastric Acid That Moves Upright of the RSI Questionnaire Measured at Baseline and in the Visit 4	At baseline and in the visit 4, after 6 weeks of treatment	The Reflux Symptom Index questionnaire examines 9 items, including stomach burning, thoracic pain, poor digestion of gastric acid that moves upright that is score from 0 to 5, with a higher score that indicates a higher severity of the symptom.
Number of Responders V4	At visit 4 after 6 weeks of treatment	A responder was defined as a patient who at the 6th week of treatment showed a reduction of at least 50% vs. the baseline and an absolute value \< 13 on the RSI questionnaire.
Score of Upper Symptoms Using the Likert Scale at Baseline and in the Visit V4	At baseline and in the visit 4	The Likert scale examines 9 symptoms, to be scored from 0 to 4, with a higher score indication a higher frequency of the symptom (i.e. 0=never, 1=occasionally, 2=sometimes, 3= often, 4=Always); The Likert scale scores of single items are as following: 1. Hoarseness or vocal problem 0 1 2 3 4 2. Throat clearance 0 1 2 3 4 3. Excess of mucus in the throat or retrosternal fall of secretions 0 1 2 3 4 4. Difficulty in swallowing food, fluids or pills 0 1 2 3 4 5. Cough after the meal or after lying 0 1 2 3 4 6. Difficulty in breathing or episodes of choking 0 1 2 3 4 7. Problematic or troublesome cough 0 1 2 3 4 8. Sensation of something blocked or mass in the throat 0 1 2 3 4 9. Stomach burning, thoracic pain, poor digestion of gastric acid that moves upright 0 1 2 3 4. Subscales are summarized to compute a total score (total score ranges from 0-36). The mean values of Likert scale total score are reported.
Presence of Upper Symptoms at Visit 4, Using the RSI Questionnaire	At visit 4 after weeks of treatment	The Reflux Symptom Index questionnaire examines 9 items, to be scored from 0 to 5, with a higher score indication a higher severity of the symptom (range of total score: 0-45).
Use of Rescue Medication (Omeprazole) During the Treatment	From baseline to visit 4	In the first 6 weeks of treatment, the intake in each treatment group of the rescue medication, allowed or not allowed, was calculated as the frequency of intake of the specific drug and the comparison between groups was performed using the Fisher's exact test.
Use of Rescue Medication (Omeprazole) During the Follow-up	In the Visit 6 after 12 weeks from baseline	During the follow-up, the intake in each treatment group of the rescue medication, allowed or not allowed, was calculated as the frequency of intake of the specific drug.
Use of Rescue Medication (Other Than Omeprazole) During Treatment	From baseline to visit 4	During treatment, the intake in each treatment group of the rescue medication, allowed or not allowed, was calculated as the frequency of intake of the specific drug.
Patients'Satisfaction	At visit 4 after weeks of treatment	This evaluation was expressed with a semi-quantitative ordinal scale: 0 = low, 1 = discrete, 2 = good, 3 = excellent).
Score of Sensation of Something Blocked or Mass in the Throat of the RSI Questionnaire Measured at Baseline and in the Visit 4	At baseline and in the visit 4, after 6 weeks of treatment	The Reflux Symptom Index questionnaire examines 9 items, including sensation of something blocked or mass in the throat that is score from 0 to 5, with a higher score that indicates a higher severity of the symptom.

Countries

Italy

Participant flow

Recruitment details

A first specialist visit was performed by an ENT as per clinical practice based on patient's symptoms. Patients sent by the ENT should not have been pre-treated with PPIs and/or medical devices and/or similar products. The diagnosis was confirmed by the Gastroenterologist Investigator who recruited patients.

Pre-assignment details

In this phase of the study, 72 patients were enrolled. One patient withdrew the informed consent and was excluded from the study before randomization.

Participants by arm

Arm	Count
GERDOFF® + Omeprazole GERDOFF® (tablets) was orally administered 3 times per day after meals; omeprazole was orally administered once a day before breakfast (2 capsules). The treatment lasted 6 weeks (+/- 2 days). GERDOFF®: GERDOFF® Hyaluronic acid + chondroitin sulphate + hydroxide aluminium Melt-in-mouth tablet 1100 mg	35
Omeprazole Omeprazole was orally administered once a day before breakfast (2 capsules). The treatment lasted 6 weeks (+/- 2 days). Omeprazole: Omeprazole, 2 capsules 20 mg, once a day before breakfast	36
Total	71

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	1	1
Overall Study	Withdrawal by Subject	12	1

Baseline characteristics

Characteristic	Omeprazole	GERDOFF® + Omeprazole	Total
Age, Continuous	45.0 years	46.0 years	46.0 years
Body Mass Index	22.7 kg/m^2	22.6 kg/m^2	22.7 kg/m^2
Cough after the meal or after lying no	21 participants	22 participants	43 participants
Cough after the meal or after lying yes	15 participants	13 participants	28 participants
Difficulty in breathing or episodes of choking no	31 participants	31 participants	62 participants
Difficulty in breathing or episodes of choking yes	5 participants	4 participants	9 participants
Difficulty in swallowing food, fluids or pills no	29 participants	28 participants	57 participants
Difficulty in swallowing food, fluids or pills yes	7 participants	7 participants	14 participants
Excess of mucus in the throat or retrosternal fall of secretions no	21 participants	21 participants	42 participants
Excess of mucus in the throat or retrosternal fall of secretions yes	15 participants	14 participants	29 participants
Hoarseness or vocal problem no	18 participants	14 participants	32 participants
Hoarseness or vocal problem yes	18 participants	21 participants	39 participants
Number of symptoms	4 Symptom	4 Symptom	4 Symptom
Patients with simultaneous symptoms 1 symptom	3 participants	2 participants	5 participants
Patients with simultaneous symptoms 2 symptoms	1 participants	5 participants	6 participants
Patients with simultaneous symptoms 3 symptoms	6 participants	9 participants	15 participants
Patients with simultaneous symptoms 4 symptoms	17 participants	11 participants	28 participants
Patients with simultaneous symptoms 5 symptoms	5 participants	5 participants	10 participants
Patients with simultaneous symptoms 6 symptoms	3 participants	2 participants	5 participants
Patients with simultaneous symptoms 7 symptoms	1 participants	1 participants	2 participants
Problematic or troublesome cough no	24 participants	19 participants	43 participants
Problematic or troublesome cough yes	12 participants	16 participants	28 participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	36 Participants	35 Participants	71 Participants
Sensation of something blocked or mass in the throat no	24 participants	18 participants	42 participants
Sensation of something blocked or mass in the throat yes	12 participants	17 participants	29 participants
Sex: Female, Male Female	32 Participants	22 Participants	54 Participants
Sex: Female, Male Male	4 Participants	13 Participants	17 Participants
Stomach burning, thoracic pain, poor digestion of gastric acid that moves upright no	14 participants	18 participants	32 participants
Stomach burning, thoracic pain, poor digestion of gastric acid that moves upright yes	22 participants	17 participants	39 participants
Throat clearance no	13 participants	17 participants	30 participants
Throat clearance yes	23 participants	18 participants	41 participants
Weight	62.0 kg	63.0 kg	62.5 kg

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 35	0 / 36
other Total, other adverse events	14 / 35	12 / 36
serious Total, serious adverse events	0 / 35	1 / 36

Outcome results

Primary

Change From Baseline to Visit V4 of the Total Score of RSI Questionnaire

After 6 weeks of treatment, the changes from baseline in the score of Reflux Symptom Index questionnaire were evaluated to verify the effects of treatments on high symptoms. The RSI questionnaire examines 9 items that are scored from 0 to 5, with a higher score that indicates a higher severity of the symptom (range of total score: 0-45).

Time frame: In the first visit (baseline) and in the visit 4 (after 6 weeks of treatment)

Population: Four patients in the GERFOFF + omeprazole group did not complete the Reflux Symptom Index questionnaire and could not be included in the analysis.

Arm	Measure	Value (MEAN)	Dispersion
GERDOFF® + Omeprazole	Change From Baseline to Visit V4 of the Total Score of RSI Questionnaire	-16.2 Score on a scale	Standard Deviation 7.45
Omeprazole	Change From Baseline to Visit V4 of the Total Score of RSI Questionnaire	-13.7 Score on a scale	Standard Deviation 10.58

p-value: 0.27695% CI: [-7.03, 2.04]Unpaired t test

Secondary

Number of Responders V4

A responder was defined as a patient who at the 6th week of treatment showed a reduction of at least 50% vs. the baseline and an absolute value \< 13 on the RSI questionnaire.

Time frame: At visit 4 after 6 weeks of treatment

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
GERDOFF® + Omeprazole	Number of Responders V4	Yes	23 Participants
GERDOFF® + Omeprazole	Number of Responders V4	No	8 Participants
Omeprazole	Number of Responders V4	Yes	20 Participants
Omeprazole	Number of Responders V4	No	16 Participants

p-value: 0.0496Chi-squared

Secondary

Number of Responders V6

Responder patients of Group Gerdoff® + omeprazole were randomly assigned to receive a treatment with Gerdoff®-one tablet three times daily- All patients received a packaging of omeprazole, to be taken only if necessary, at constant dose and according to the indications of the Investigator. The scheduled duration of the follow-up period was 12 weeks. A responder was defined as a patient who at the 6th week of treatment showed a reduction of at least 50% vs. the baseline and an absolute value \< 13 on the RSI questionnaire.

Time frame: In the Visit 6 at the end of follow-up

Arm	Measure	Category	Value (COUNT_OF_PARTICIPANTS)
GERDOFF® + Omeprazole	Number of Responders V6	yes	9 Participants
GERDOFF® + Omeprazole	Number of Responders V6	No	0 Participants
Omeprazole	Number of Responders V6	No	1 Participants
Omeprazole	Number of Responders V6	yes	7 Participants

Secondary

Patients'Satisfaction

This evaluation was expressed with a semi-quantitative ordinal scale: 0 = low, 1 = discrete, 2 = good, 3 = excellent).

Time frame: At visit 4 after weeks of treatment

Population: Four patients in the GERFOFF + omeprazole group did not complete the Reflux Symptom Index questionnaire and could not be included in the analysis.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
GERDOFF® + Omeprazole	Patients'Satisfaction	Discrete	1 Participants
GERDOFF® + Omeprazole	Patients'Satisfaction	Good	11 Participants
GERDOFF® + Omeprazole	Patients'Satisfaction	Low	3 Participants
GERDOFF® + Omeprazole	Patients'Satisfaction	Excellent	15 Participants
GERDOFF® + Omeprazole	Patients'Satisfaction	Missing	1 Participants
Omeprazole	Patients'Satisfaction	Excellent	17 Participants
Omeprazole	Patients'Satisfaction	Missing	0 Participants
Omeprazole	Patients'Satisfaction	Low	1 Participants
Omeprazole	Patients'Satisfaction	Good	11 Participants
Omeprazole	Patients'Satisfaction	Discrete	7 Participants

Secondary

Presence of Upper Symptoms at Visit 4, Using the RSI Questionnaire

The Reflux Symptom Index questionnaire examines 9 items, to be scored from 0 to 5, with a higher score indication a higher severity of the symptom (range of total score: 0-45).

Time frame: At visit 4 after weeks of treatment

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
GERDOFF® + Omeprazole	Presence of Upper Symptoms at Visit 4, Using the RSI Questionnaire	Missing	1 Participants
GERDOFF® + Omeprazole	Presence of Upper Symptoms at Visit 4, Using the RSI Questionnaire	4 symptoms	4 Participants
GERDOFF® + Omeprazole	Presence of Upper Symptoms at Visit 4, Using the RSI Questionnaire	1 symptom	7 Participants
GERDOFF® + Omeprazole	Presence of Upper Symptoms at Visit 4, Using the RSI Questionnaire	5 symptoms	0 Participants
GERDOFF® + Omeprazole	Presence of Upper Symptoms at Visit 4, Using the RSI Questionnaire	3 symptoms	13 Participants
GERDOFF® + Omeprazole	Presence of Upper Symptoms at Visit 4, Using the RSI Questionnaire	6 symptoms	0 Participants
GERDOFF® + Omeprazole	Presence of Upper Symptoms at Visit 4, Using the RSI Questionnaire	2 symptoms	6 Participants
Omeprazole	Presence of Upper Symptoms at Visit 4, Using the RSI Questionnaire	6 symptoms	1 Participants
Omeprazole	Presence of Upper Symptoms at Visit 4, Using the RSI Questionnaire	Missing	4 Participants
Omeprazole	Presence of Upper Symptoms at Visit 4, Using the RSI Questionnaire	1 symptom	2 Participants
Omeprazole	Presence of Upper Symptoms at Visit 4, Using the RSI Questionnaire	2 symptoms	9 Participants
Omeprazole	Presence of Upper Symptoms at Visit 4, Using the RSI Questionnaire	3 symptoms	11 Participants
Omeprazole	Presence of Upper Symptoms at Visit 4, Using the RSI Questionnaire	4 symptoms	7 Participants
Omeprazole	Presence of Upper Symptoms at Visit 4, Using the RSI Questionnaire	5 symptoms	2 Participants

Secondary

Score of Cough of the RSI Questionnaire Measured at Baseline and in the Visit 4 After the Meal or After Lying

The Reflux Symptom Index questionnaire examines 9 items, including cough that is score from 0 to 5, with a higher score that indicates a higher severity of the symptom.