Clinical Trials Register

Summary
EudraCT Number:	2017-002708-28
Sponsor's Protocol Code Number:	REDIV/002/17
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-12-22
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2017-002708-28

A.3

Full title of the trial

Rifaximin delayed release (400 mg tablet) for the prevention of recurrent acute diverticulitis and diverticular complications. A phase II, multicenter, double-blind, placebo-controlled, randomized clinical trial.

Rifaximin (400 mg Tabletten) mit verzögerter Freisetzung zur Prävention einer wiederkehrenden akuten Divertikulitis und damit zusammenhängenden Komplikationen.
Eine multizentrische, doppel-blinde, Plazebo-kontrollierte, randomisierte klinische Prüfung der Phase II (ROAD Studie).

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Rifaximin tablets in the prevention of recurrent acute diverticulitis and diverticular complications.

Rifaximin Tabletten zur Prävention wiederauftretender akuter Divertikulitis und damit verbundener Komplikationen.

A.3.2

Name or abbreviated title of the trial where available

"The ROAD Trial"

A.4.1

Sponsor's protocol code number

REDIV/002/17

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Alfasigma S.p.a
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Alfasigma SpA
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Alfasigma SpA
B.5.2	Functional name of contact point	Corporate R&D
B.5.3	Address:
B.5.3.1	Street Address	Via Ragazzi del '99 n° 5
B.5.3.2	Town/ city	Bologna
B.5.3.3	Post code	40133
B.5.3.4	Country	Italy
B.5.4	Telephone number	390516489619
B.5.5	Fax number	390516489671
B.5.6	E-mail	alessandro.ble@alfasigma.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Rifaximin EIR
D.3.2	Product code	Rifaximin EIR
D.3.4	Pharmaceutical form	Gastro-resistant tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RIFAXIMIN
D.3.9.1	CAS number	80621-81-4
D.3.9.2	Current sponsor code	Rifaximin-EIR
D.3.9.3	Other descriptive name	RIFAXIMINA
D.3.9.4	EV Substance Code	SUB10312MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	400
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Gastro-resistant tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Prevention of recurrent acute diverticulitis and diverticular complications

E.1.1.1

Medical condition in easily understood language

Prevention of episodes of inflammation to diverticula and its complications

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10052812
E.1.2	Term	Acute diverticulitis
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of the study is to demonstrate that the rate of patients with recurrence/complications of diverticulitis is statistically different between patients treated with any of the two doses of Rifaximin-EIR and patients treated with placebo.

E.2.2

Secondary objectives of the trial

The secondary objectives of the study are:
 to demonstrate that Rifaximin-EIR 400 mg b.i.d. and placebo are statistically different in terms of rate of patients with recurrence/complications of diverticulitis.
 to demonstrate that Rifaximin-EIR 800 mg b.i.d. and placebo are statistically different in terms of rate of patients with recurrence/complications of diverticulitis.
 to demonstrate that Rifaximin-EIR 800 mg b.i.d. and Rifaximin-EIR 400 mg b.i.d. are statistically different in terms of rate of patients with recurrence/complications of diverticulitis.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Men and women aged 18-80 years at screening visit (V1).
2) Female participants must be:
•of non-childbearing potential, i.e.: i) post-menopausal (at least 2 years without spontaneous menses), or ii) surgically sterile (bilateral tubal occlusion, or hysterectomy), or iii) ablation of both ovaries)
or
•of childbearing potential with a negative pregnancy test result at screening and randomization AND agreeing to use a highly effective method of contraception (i.e. with failure rate of less than 1% per year) until 72 hours after the last dose of investigational drug of the entire study.
Note 1: Based on Clinical Trial Facilitation Group recommendations, highly effective methods of contraception are the following:
i)intrauterine device (IUD);
ii)intrauterine hormone-releasing systems (IUS); or;
iii)combined hormonal contraceptives (i.e. estrogen and progestogen) in oral, intravaginal or transdermal form, with inhibition of ovulation as primary mode of action; or
iv)progestogen-only hormonal contraceptives in oral, injectable or implantable form, with inhibition of ovulation as primary mode of action; or
v)absolute and continuous sexual abstinence.
Note 2: In each case of delayed menstrual period (over one months between menstruations), female participants of child-bearing potential will be strongly recommended a confirmation of absence of pregnancy. This recommendation applies also to women of child-bearing potential with infrequent or irregular menstrual cycles.
3)A previous documented episode of diverticulitis between 30 and 180 days prior to screening (V1).
Diverticulitis is defined as the presence of
•abdominal pain or tenderness
plus
•at least one of the following:
fever or
leukocytosis and/or high serum C-Reactive Protein (CRP) levels (above the upper limit of normal)
plus
•diagnosis confirmation with imaging of diverticulitis at computed tomography (CT), ultrasound (US) or colonoscopy. Note: per scientific guidelines, colonoscopy is not recommended and will not be accepted to diagnose acute diverticulitis recurrence throughout the study, however a colonoscopy diagnosis of acute diverticulitis can be accepted retrospectively for enrolment purposes only.
4)Patients must be in clinical remission from acute diverticulitis at the screening (V1). Patients with symptomatic uncomplicated diverticular disease (SUDD, i.e. patients with mild abdominal pain or tenderness but no clinically significant inflammation (i.e. no increased number of leukocytes) at screening (V1) can be enrolled.
5)Patients accepting to provide and legally capable of providing free and informed consent to all procedures included in the protocol

E.4

Principal exclusion criteria

1) History of 2 or more acute diverticulitis episodes or history of any diverticular complication.
2)Any documented current organic disease of the gastrointestinal tract other than diverticulosis (including but not limited to: severe esophagitis, active peptic ulcer, acute gastritis, pancreatitis, hepatitis, cancer, angiodysplasia, familial adenomatous polyposis, intestinal obstruction [including partial intestinal obstruction], any enteritis [also including those associated with fever and/or bloody stools], etc.).
3)Laboratory signs of significant acute inflammation (consistent with unresolved diverticulitis) or signs/ symptoms of diverticular complications.
4)Diagnosis or history of inflammatory bowel disease (or other conditions associated with ulcerative lesions of the intestinal tract).
5)History of polypectomy for early colon cancer confirmed after polypectomy or history of any large bowel (including anal canal) or small bowel resection for any reason. Patients with history of polypectomy for non-cancerous adenomas only can be enrolled.
6)Patients with positive Clostridium difficile toxin stool assay.
7)Health conditions requiring continuous or intermittent treatment with systemic steroids and/or biologic or non-biologic immunosuppressive or immunomodulatory agents (e.g. autoimmune diseases, etc.).
8)Use of marketed rifaximin (or neomycin or other low-absorbable oral antibiotics) during or after the previous episode of acute diverticulitis.
9) Treatment with the following drugs within 28 days prior to randomization: pharmaceutical probiotics (functional food is allowed), systemic antibiotics, mesalazine (a.k.a. mesalamine, 5-ASA), NSAIDs (also including aspirin greater than 100 mg a day), opioid drugs, warfarin (or other Coumarins), systemic steroids (inhaled steroids are permitted), cyclosporine or any other non-biologic immunosuppressive or immunomodulatory agent.
10) Biologic immunosuppressive or immunomodulatory agent within 180 days prior to randomization (V2).
11) Cancer (excluding non-melanoma skin cancer) and/or need of any anti-cancer treatment (also including radiotherapy) within 5 years.
12) Severe hepatic impairment (i.e. Child-Pugh B or C).
13) Severe kidney impairment (i.e. estimated glomerular filtration rate (GFR) <30 ml/min).
14) Any other current significant health condition (e.g. cardiovascular, respiratory, renal, hepatic, neurologic, psychiatric, hematologic, oncologic, immune, muscle and joint, etc.) that in the Investigator’s judgement may:
i) jeopardize the patient’s safe participation in the trial; or
ii) make unlikely the patient’s completion of the study; or
iii) make unlikely the patient’s compliance with the study procedures (e.g. highly anticipated need of non-permitted treatments, significant disability, terminal illness, etc.).
15) History of hypersensitivity to rifaximin, rifamycin-derivatives or any of the rifaximin delayed release or placebo excipients (see list in the protocol).
16) History of any alcohol or drug abuse or dependence within the last year.
17) Women who are pregnant, breast-feeding or planning a pregnancy during the trial period.
18) Subjects who have participated in another drug clinical trial/taken any other investigational drug within 6 months prior to randomization.

E.5 End points

E.5.1

Primary end point(s)

Rate of patients with recurrence of diverticulitis or diverticular
complications over the 12-month treatment period.
Definitions:
a) Diverticulitis is defined as the presence of
 abdominal pain or tenderness at physical examination
plus
at least one of the following:
 fever
 leukocytosis and/or C-reactive Protein (CRP) above the upper limit of normal
plus
 diagnosis confirmation with imaging of diverticulitis at CT or US.
b) Recurrent diverticulitis defined as a new episode of diverticulitis after previous clinical remission.
c) Diverticular complications are the following: diverticula-associated bleeding, abscess, fistula, perforation, peritonitis, obstruction. Complications will be diagnosed and documented per specific center procedures.
Primary endpoint and event date will be adjudicated by the Investigator based on the collected documentation.

E.5.1.1

Timepoint(s) of evaluation of this end point

During 12 months of treatment

E.5.2

Secondary end point(s)

Rate of patients who, over the 12-month treatment period, have had an acute episode of prolonged (at least 24 hours) left lower quadrant abdominal pain plus concomitant leukocytosis or elevation of serum CRP (i.e. above the upper limit of normal) with or without CT or US imaging confirming acute diverticulitis.
Additional secondary endpoints (evaluated throughout the entire study treatment period)
 Time to diverticulitis recurrence/complication.
 Rate of patients with diverticulitis-associated fever as a component of the primary endpoint.
Change from baseline of the following symptoms will be assessed:
 left-lower quadrant abdominal pain (intensity and duration of episodes).
 bowel habits.
 Number of days in a year with left-lower quadrant abdominal pain, number of days in a year with any abdominal pain, number of weeks in a year with episodes of left-lower quadrant abdominal pain lasting ≥24 hours, and number of weeks in a year with bloating.
 Rate of any hospitalization for diverticulitis.
Rate of hospitalization for diverticulitis without surgery.
 Rate of elective surgery for diverticulitis.
 Rate of emergency surgery for diverticulitis.
 Change in Quality of Life.
Exploratory secondary endpoint
Change in faecal calprotectin levels (only in selected sites).

E.5.2.1

Timepoint(s) of evaluation of this end point

During 12 months of treatment

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

110

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

133

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

749

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

882

F.4.2.2

In the whole clinical trial

882

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients will be submitted to a follow-up visit after 2 weeks from treatment end.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-05-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-08-28

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-12-22

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